-
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 -
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 -
Cancer Treatment Reviews Nov 2022The objective of this study was to estimate the relative efficacy and safety of targeted therapies for the treatment of metastatic melanoma using a network meta-analysis... (Meta-Analysis)
Meta-Analysis Review
Comparative efficacy and safety of targeted therapies for BRAF-mutant unresectable or metastatic melanoma: Results from a systematic literature review and a network meta-analysis.
BACKGROUND
The objective of this study was to estimate the relative efficacy and safety of targeted therapies for the treatment of metastatic melanoma using a network meta-analysis (NMA).
METHODS
A systematic literature review (SLR) identified studies in Medline, Embase and Cochrane published until November 2020. Screening used prespecified eligibility criteria. Following a transitivity assessment across included studies, Bayesian NMA was conducted.
RESULTS
A total of 43 publications reporting 15 targeted therapy trials and 42 reporting 18 immunotherapy trials were retained from the SLR and considered for the NMA. Due to substantial between-study heterogeneity with immunotherapy trials, the analysis considered a network restricted to targeted therapies. Among combination therapies, encorafenib + binimetinib was superior to dabrafenib + trametinib for overall response rate (OR = 1.86; 95 % credible interval [CrI] 1.10, 3.17), superior to vemurafenib + cobimetinib with fewer serious adverse events (SAEs) (OR = 0.51; 95 % CrI 0.29, 0.91) and fewer discontinuations due to AEs (OR = 0.45; 95 % CrI 0.21, 0.96), and superior to atezolizumab + vemurafenib + cobimetinib with fewer SAEs (OR = 0.41; 95 % CrI 0.21, 0.82). Atezolizumab + vemurafenib + cobimetinib and encorafenib + binimetinib were generally comparable for efficacy endpoints. Among double combination therapies, encorafenib + binimetinib showed high probabilities of being better for all efficacy and safety endpoints.
CONCLUSIONS
This NMA confirms that combination therapies are more efficacious than monotherapies. Encorafenib + binimetinib has a favourable efficacy profile compared to other double combination therapies and a favourable safety profile compared to both double and triple combination therapies.
Topics: Antineoplastic Combined Chemotherapy Protocols; Bayes Theorem; Benzimidazoles; Carbamates; Humans; Melanoma; Mutation; Neoplasms, Second Primary; Network Meta-Analysis; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Sulfonamides; Vemurafenib
PubMed: 36099854
DOI: 10.1016/j.ctrv.2022.102463 -
European Journal of Medical Research Aug 2023The aim of this study was to evaluate the efficacy and safety of osimertinib for the treatment of leptomeningeal metastases (LM) from epidermal growth factor receptor... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The aim of this study was to evaluate the efficacy and safety of osimertinib for the treatment of leptomeningeal metastases (LM) from epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC).
METHODS
We conducted a systematic review and meta-analysis to aggregate the clinical outcomes of patients with LM from EGFR-mutant NSCLC treated with osimertinib. A comprehensive literature search for published and unpublished studies was implemented in April 2021 of PubMed, EMBASE, the Cochrane Library, and several international conference databases, in accordance with the PRISMA guidelines. Meta-analysis of proportions was conducted to calculate the pooled rate of overall response rate (ORR), disease control rate (DCR), one-year overall survival (OS), and adverse events (AEs).
RESULTS
A total of eleven studies (five prospective and six retrospective) including 353 patients were included. The majority of patients (346/353, 98.0%) received osimertinib as ≥ 2nd-line treatment for LM, either at a dosage of 80 mg (161/353, 45.6%) or 160 mg (191/353, 54.1%). The pooled rates of ORR and DCR were 42% (95% CI 24% to 59%) and 93% (95% CI 88% to 97%), respectively. The pooled one-year OS rate was 59% (95% CI 53% to 65%) in 233 patients from five studies. The highest incidence of AEs of all grades was rash (53%), followed by diarrhea (45%), paronychia (35%), decreased appetite (35%), and dry skin (27%), based on data from four studies.
CONCLUSIONS
Our study highlighted and confirmed the meaningful efficacy and a manageable safety profile of osimertinib for the treatment of LM from EGFR-mutant advanced NSCLC.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Retrospective Studies; Prospective Studies; Antineoplastic Agents; ErbB Receptors; Protein Kinase Inhibitors; Mutation
PubMed: 37542339
DOI: 10.1186/s40001-023-01219-y -
Aging Sep 2023Hepatocellular Carcinoma (HCC) is one of the most common malignant cancers in humans and has a high fatality rate. In recent years, researchers have verified that the...
BACKGROUNDS
Hepatocellular Carcinoma (HCC) is one of the most common malignant cancers in humans and has a high fatality rate. In recent years, researchers have verified that the Wnt/β-catenin signaling pathway affects the clinicopathological features and prognosis of patients with HCC. Although many studies have investigated the relationship between Wnt/β-catenin signaling pathway and HCC, the prognostic value of β-catenin in HCC remains inconclusive. (Catenin Beta-1) is an important factor in the Wnt/β-catenin signaling pathway. However, no consensus has been reached on the clinical and prognostic significance of mutations in HCCs.
METHODS
Eligible studies and relevant data were obtained from PubMed, Web of Science, Elsevier, Cochrane Library, Ovid, and Embase databases. The correlation between mutations and clinical/prognosis of patients were evaluated. A fixed- or random-effects model was used to calculate pooled odds ratios (OR) and 95% confidence intervals (CI).
RESULTS
Seventeen studies matched the selection criteria, and 1828 patients were included. This meta-analysis demonstrated that patients with HCC with mutations had favorable clinicopathological features and survival. The combined ORs of 1-, 3- and 5-year overall survival were0.52 (n = 6 studies, 95% CI: 0.34-0.81, Z = 2.89, =0.004, 0.28 (n =6 studies, 95% CI: 0.18-0.42, Z = 6.03, <0.00001), -0.22 (n = 6 studies, 95% CI: 0.37-0.06, Z = 2.78, = 0.005), respectively. Additionally, mutation might be significantly associated with differentiation (OR = 0.54, 95% CI:0.36-0.81, Z = 2.98, = 0.003), TMN stages (Tumor, Node, Metastasis staging classification) (OR = -0.25, 95% CI:-0.33--0.18, Z = 6.60, <0.00001), liver cirrhosis (OR = 0.21, 95% CI:0.11-0.39, Z = 4.94, < = 0.00001), and HBV (Hepatitis B Virus) infection (OR = 0.44, 95% CI:0.31-0.64, Z = 4.37, <0.0001), but not with tumor size, metastasis, vascular invasion, and HCV infection.
CONCLUSIONS
mutation can serve as an indicator of favorable prognosis as well as a novel target for treatment in HCC.
PubMed: 37733676
DOI: 10.18632/aging.205047 -
Antibiotics (Basel, Switzerland) Aug 2021is now recognized as a commonly reported sexually transmitted pathogen, and the increasing drug resistance of has become a serious public health problem. The accuracy... (Review)
Review
BACKGROUND
is now recognized as a commonly reported sexually transmitted pathogen, and the increasing drug resistance of has become a serious public health problem. The accuracy of molecular detection for detecting moderate-level azithromycin resistance is not well-established. We summarized the data from studies of the 23S rRNA mutation at position 2611 with azithromycin resistance to determine the relationship between the mutation and resistance.
METHODS AND FINDINGS
In this systematic review and meta-analysis, two researchers independently searched six databases for studies with data for the azithromycin minimum inhibitory concentrations (MICs) and the 23S rRNA mutation C2611T of each isolate. Since the breakpoint of moderate-level resistance to azithromycin (ML-AzmR) was not determined, we divided the moderate level into two groups according to the range of MICs (moderate resistance limited to 2-128 mg/L or 4-128 mg/L) for data extraction. A random-effects model was used to calculate the pooled sensitivity rate, the specificity rate, the pooled positive likelihood ratio (PLR), the negative likelihood ratio (NLR), and the diagnostic odds ratio (DOR). Meta-regression analyses by detection method, isolates sampling (a random sample or not), location, and sample size were performed to explore the possible causes of heterogeneity. The potential publication bias of the included studies was conducted by the Deeks' test. We included 20 studies in our study: 20 studies have data of with MICs between 2 and 128 mg/L with mutation or without mutation at position 2611(4759 samples), and 14 studies have data of with MICs between 4 and 128 mg/L (3367 samples). In the group with the moderate level of 2-128 mg/L, the pooled sensitivity rate of the molecular assays was determined to be 71.9% (95% CI, 67.6-74%), the pooled specificity rate was 98.7% (95% CI, 98.2-99.0%), and the DOR ranged from 55.0 to 351.3 (mean, 139.1). In the 4-128 mg/L group, the pooled sensitivity rate was 91.9% (95% CI, 88.9-94.2%), the pooled specificity rate was 95.9% (95% CI, 95.1-96.6%), and the DOR ranged from 41.9 to 364.1 (mean, 123.6).
CONCLUSION
Through this meta-analysis, we found that the C2611T mutation of 23S rRNA is valuable for the molecular diagnostic of moderate-level azithromycin resistance (ML-AzmR) in , especially when the moderate level is set at 4-128 mg/L. This rapid molecular detection method can be used for the rapid identification of ML-AzmR isolates in the clinic.
PubMed: 34572609
DOI: 10.3390/antibiotics10091027 -
Clinical and Experimental Medicine Jan 2024Activated phosphoinositide 3-kinase delta syndrome (APDS) is a rare genetic disorder that presents clinically as a primary immunodeficiency. Clinical presentation of...
Activated phosphoinositide 3-kinase delta syndrome (APDS) is a rare genetic disorder that presents clinically as a primary immunodeficiency. Clinical presentation of APDS includes severe, recurrent infections, lymphoproliferation, lymphoma, and other cancers, autoimmunity and enteropathy. Autosomal dominant variants in two independent genes have been demonstrated to cause APDS. Pathogenic variants in PIK3CD and PIK3R1, both of which encode components of the PI3-kinase, have been identified in subjects with APDS. APDS1 is caused by gain of function variants in the PIK3CD gene, while loss of function variants in PIK3R1 have been reported to cause APDS2. We conducted a review of the medical literature and identified 256 individuals who had a molecular diagnosis for APDS as well as age at last report; 193 individuals with APDS1 and 63 with APDS2. Despite available treatments, survival for individuals with APDS appears to be shortened from the average lifespan. A Kaplan-Meier survival analysis for APDS showed the conditional survival rate at the age of 20 years was 87%, age of 30 years was 74%, and ages of 40 and 50 years were 68%. Review of causes of death showed that the most common cause of death was lymphoma, followed by complications from HSCT. The overall mortality rate for HSCT in APDS1 and APDS2 cases was 15.6%, while the mortality rate for lymphoma was 47.6%. This survival and mortality data illustrate that new treatments are needed to mitigate the risk of death from lymphoma and other cancers as well as infection. These analyses based on real-world evidence gathered from the medical literature comprise the largest study of survival and mortality for APDS to date.
Topics: Adult; Humans; Young Adult; Class I Phosphatidylinositol 3-Kinases; Immunologic Deficiency Syndromes; Lymphoma; Mutation; Neoplasms; Phosphatidylinositol 3-Kinase; Phosphatidylinositol 3-Kinases; Primary Immunodeficiency Diseases; Survival Rate; Middle Aged
PubMed: 38280023
DOI: 10.1007/s10238-023-01259-y -
European Journal of Medical Research Jun 2021Coronavirus Disease-2019 (SARS-CoV-2) started its devastating trajectory into a global pandemic in Wuhan, China, in December 2019. Ever since, several variants of...
INTRODUCTION
Coronavirus Disease-2019 (SARS-CoV-2) started its devastating trajectory into a global pandemic in Wuhan, China, in December 2019. Ever since, several variants of SARS-CoV-2 have been identified. In the present review, we aimed to characterize the different variants of SARS-CoV-2 and explore the related morbidity and mortality.
METHODS
A systematic review including the current evidence related to different variants of SARS-CoV-2 and the related morbidity and mortality was conducted through a systematic search utilizing the keywords in the online databases including Scopus, PubMed, Web of Science, and Science Direct; we retrieved all related papers and reports published in English from December 2019 to September 2020.
RESULTS
A review of identified articles has shown three main genomic variants, including type A, type B, and type C. we also identified three clades including S, V, and G. Studies have demonstrated that the C14408T and A23403G alterations in the Nsp12 and S proteins are the most prominent alterations in the world, leading to life-threatening mutations.The spike D614G amino acid change has become the most common variant since December 2019. From missense mutations found from Gujarat SARS-CoV-2 genomes, C28854T, deleterious mutation in the nucleocapsid (N) gene was significantly associated with patients' mortality. The other significant deleterious variant (G25563T) is found in patients located in Orf3a and has a potential role in viral pathogenesis.
CONCLUSION
Overall, researchers identified several SARS-CoV-2 variants changing clinical manifestations and increasing the transmissibility, morbidity, and mortality of COVID-19. This should be considered in current practice and interventions to combat the pandemic and prevent related morbidity and mortality.
Topics: COVID-19; Coronavirus RNA-Dependent RNA Polymerase; Humans; Morbidity; Mutation; Pandemics; SARS-CoV-2; Spike Glycoprotein, Coronavirus; Survival Rate; Virulence
PubMed: 34103090
DOI: 10.1186/s40001-021-00524-8 -
Neurologia Medico-chirurgica Apr 2022Malignant progression of diffuse low-grade glioma (LGG) is a critical event affecting patient survival; however, the incidence and related factors have been inconsistent... (Meta-Analysis)
Meta-Analysis
Malignant progression of diffuse low-grade glioma (LGG) is a critical event affecting patient survival; however, the incidence and related factors have been inconsistent in literature. According to the PRISMA guidelines, we systematically reviewed articles from 2009, meta-analyzed the incidence of malignant progression, and clarified factors related to the transformation. Forty-one articles were included in this study (n = 7,122; n, number of patients). We identified two definitions of malignant progression: histologically proven (Htrans) and clinically defined (Ctrans). The malignant progression rate curves of Htrans and Ctrans were almost in parallel when constructed from the results of meta-regression by the mean follow-up time. The true transformation rate was supposed to lie between the two curves, approximately 40% at the 10-year mean follow-up. Risk of malignant progression was evaluated using hazard ratio (HR). Pooled HRs were significantly higher in tumors with a larger pre- and postoperative tumor volume, lower degree of resection, and notable preoperative contrast enhancement on magnetic resonance imaging than in others. Oligodendroglial histology and IDH mutation (IDHm) with 1p/19q codeletion (Codel) also significantly reduced the HRs. Using Kaplan-Meier curves from eight studies with molecular data, we extracted data and calculated the 10-year malignant progression-free survival (10yMPFS). The 10yMPFS in patients with IDHm without Codel was 30.4% (95% confidence interval [95% CI]: 22.2-39.0) in Htrans and 38.3% (95% CI: 32.3-44.3) in Ctrans, and that with IDHm with Codel was 71.7% (95% CI: 61.7-79.5) in Htrans and 62.5% (95% CI: 55.9-68.5) in Ctrans. The effect of adjuvant radiotherapy or chemotherapy could not be determined.
Topics: Brain Neoplasms; Glioma; Humans; Incidence; Isocitrate Dehydrogenase; Mutation
PubMed: 35197400
DOI: 10.2176/jns-nmc.2021-0313 -
International Immunopharmacology Nov 2022To investigate the clinical benefits of combination therapy with immune checkpoint inhibitors (ICIs) and best combination regimen for people with advanced hepatocellular... (Meta-Analysis)
Meta-Analysis Review
Benefits of combination therapy with immune checkpoint inhibitors and predictive role of tumour mutation burden in hepatocellular carcinoma: A systematic review and meta-analysis.
OBJECTIVES
To investigate the clinical benefits of combination therapy with immune checkpoint inhibitors (ICIs) and best combination regimen for people with advanced hepatocellular carcinoma (HCC) and to explore the predictive performance of tumour mutation burden (TMB).
METHODS
We conducted a systematic literature search to identify clinical trials. Meta-analysis and subgroup analyses were performed to estimate the benefits of combination regimens with PD-1/PD-L1 inhibitors for patients with advanced HCC and compare the effectiveness of PD-1/PD-L1 inhibitors and sorafenib as first-line therapy. Individualized analysis and Kaplan-Meier were used to assess the prognostic value of TMB.
RESULTS
A total of 29 studies with 5396 patients were included. ICIs' combination therapy had higher ORR (26 % vs 15 %) and DCR (73 % vs 55 %), longer PFS (5.5 vs 3.1 months) and OS (15.9 vs 12.6 months) compared to monotherapy. Anti-PD-1/PD-L1 agents provided improved ORR, DCR, PFS and OS compared to sorafenib. The overall ORs of ORR and DCR in subgroup analysis were 3.49 (95 % CI 2.36-5.17, p < 0.01) and 1.60 (95 % CI 1.15-2.21, p < 0.01). The overall HRs of PFS and OS were 0.68 (95 % CI 0.48-0.96, p = 0.03) and 0.73 (95 % CI 0.62-0.85, p < 0.01). PD-1/PD-L1 inhibitors plus anti-VEGF agents had an advantage in DCR (0.80 vs 0.48, meta-regression = - 0.32, P < 0.001), but an equal ORR (0.29 vs 0.26) compared to dual immune checkpoint inhibitors. The total OS in Dua-ICIs were 16.5 months (95 % CI 14.2-18.7), yet not reached in the major studies of ICI plus anti-VEGF regimen. In individualized analysis, the 1-year OS was superior for patients who had high-TMB (>10, mutations/Mb) than moderate-TMB (1-10, mutations/Mb; 28 % vs 15 %, P = 0.025).
CONCLUSION
Immune checkpoint inhibitors' combination therapy improved clinical outcomes in the management of advanced hepatocellular carcinoma. However, the overall objective response rate still did not exceed 30%. PD-1/PD-L1 inhibitors plus anti-angiogenic agents and dual immunotherapy provided significantly increased survival over sorafenib, which also pose new challenges for future research, and more appropriate and guided control regimens are required. Also, TMB may be a promising prognostic biomarker for immunotherapy in HCC. However, the validation of prospective and large sample studies is needed.
Topics: Humans; B7-H1 Antigen; Carcinoma, Non-Small-Cell Lung; Immune Checkpoint Inhibitors; Carcinoma, Hepatocellular; Lung Neoplasms; Antineoplastic Agents, Immunological; Sorafenib; Prospective Studies; Liver Neoplasms; Biomarkers, Tumor; Mutation
PubMed: 36126410
DOI: 10.1016/j.intimp.2022.109244