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BMC Cancer Feb 2018Although EGFR-TKI is the preferred treatment for NSCLC patients with sensitive mutations, subsequent drug resistance is almost inevitable. The specific mechanisms of... (Meta-Analysis)
Meta-Analysis Review
Frequency of the acquired resistant mutation T790 M in non-small cell lung cancer patients with active exon 19Del and exon 21 L858R: a systematic review and meta-analysis.
BACKGROUND
Although EGFR-TKI is the preferred treatment for NSCLC patients with sensitive mutations, subsequent drug resistance is almost inevitable. The specific mechanisms of EGFR-TKI drug resistance can be identified through repeat biopsy.
METHODS
To better understand the clinical characteristics of TKI resistance in NSCLC patients, we retrospectively reviewed studies of acquired TKI drug resistance using repeat biopsy from the last decade. The relevant literature was retrieved from January 2005 to August 2015 in the databases Medline and Embase. The search terms were NSCLC or non-small cell lung cancer and T790 M.
RESULTS
A total of 478 patients with NSCLC tested by repeated biopsy were confirmed to have acquired TKI resistance. Analysis indicated that 240 patients (50.21%) of the 478 patients with acquired TKI drug resistance had the T790 M mutation. The detection rate of T790 M in different repeat biopsy sites was also different, with the highest positive rate in the lymph nodes (60%) and the lowest detection rate in cerebrospinal fluid (less than 5%). In addition, patients with T790 M had longer overall survival compared to those without the mutation (P < 0.05). Of the 240 patients with T790 M mutations, 213 patients showed results consistent with the mutation analysis before TKI treatment, and the rate of patients with the L858R point mutation along with the T790 M mutation was lower than that of patients with the exon 19 deletion (36.42% to 58.30%).
CONCLUSIONS
T790 M occurred more frequently in patients with the exon 19 deletion than in those with exon 21 L858R, which gave the survival benefit of the T790 M mutation and may explain why patients with the exon 19 deletion had an improved overall survival.
Topics: Carcinoma, Non-Small-Cell Lung; Drug Resistance, Neoplasm; ErbB Receptors; Exons; Gene Frequency; Humans; Lung Neoplasms; Mutation; Protein Kinase Inhibitors; Survival Analysis
PubMed: 29409466
DOI: 10.1186/s12885-018-4075-5 -
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 -
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 -
Infection and Drug Resistance 2019resistance to azithromycin has become a significant public health concern globally, and high-level azithromycin-resistant (HL-AzmR) isolates have emerged frequently.... (Review)
Review
BACKGROUND
resistance to azithromycin has become a significant public health concern globally, and high-level azithromycin-resistant (HL-AzmR) isolates have emerged frequently. However, high-level azithromycin resistance is considered to be caused by mutated alleles of 23S rRNA gene at position 2059, and identification of HL-AzmR isolates mainly relies on agar dilution method or E-test method. This study aimed to assess the accuracy of the molecular assays targeting the mutation A2059G for identifying HL-AzmR isolates and thereby determine the association between the mutation and high-level azithromycin resistance.
METHODS
Two researchers independently searched six databases to identify studies published from the launch of each database to October 15, 2017. The fixed effects model was used to estimate the pooled sensitivity rate, specificity rate, positive predictive value (PPV), and negative predictive value (NPV). Summary receiver operating characteristic curves were generated, and the area under the curve (AUC) was determined to estimate the overall performance of the assays. The Deeks' test was conducted to evaluate potential publication bias.
RESULTS
Ten relevant studies were included in the meta-analysis to assess the synthetic accuracy of the molecular assays. The molecular assays had the synthetic sensitivity rate of 97.8% and the synthetic specificity rate of 99.1%. And the aggregated PPV and NPV were 96.4% and 99.5%, respectively. AUC was 0.99, suggesting a close relation existing between the mutation A2059G and high-level azithromycin resistance. This indicated that the molecular assays targeting the mutation A2059G have relatively high overall accuracy for identifying HL-AzmR isolates. Publication bias was statistically significant.
CONCLUSION
The mutation A2059G is the critical factor causing high-level azithromycin resistance. Hence, molecular methods are recommended to be put into clinical practice by commercialization, which will assist clinicians to prescribe more precisely.
PubMed: 30643437
DOI: 10.2147/IDR.S183754 -
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 -
Scientific Reports Sep 2015Many types of KIT mutations have been observed in gastrointestinal stromal tumors (GISTs), but their prognostic and predictive significance are still unclear. A... (Meta-Analysis)
Meta-Analysis Review
Many types of KIT mutations have been observed in gastrointestinal stromal tumors (GISTs), but their prognostic and predictive significance are still unclear. A meta-analysis and literature review were conducted to estimate the contribution of KIT mutations in prognostic parameters and clinic-pathological significance of GISTs. A total of 18 relevant articles from PubMed, EMBASE and Web of Science databases were included in this study. The frequency of KIT mutation was significantly increased in the GIST patients with higher mitosis (≥5/50 high-power fields (HPFs) and larger size (≥5 cm) of tumors than in those with lower MI (≤5/50HPFs) and smaller size (≤5 cm) of GISTs respectively. The rate of KIT mutation was not significantly changed between GISTs in stomachs and in small intestines. KIT mutational status has prognostic significance for patients' outcome. GIST patients with KIT exon 9 mutations have higher risk of progression than those with exon 11 mutations. 5 year relapse-free survival (RFS) rate was significantly higher in patients with KIT exon 11 deletion than in those with other type of KIT exon 11 mutations. The deletion involving KIT exon 11, particularly codons 557-558, is a valuable predictor of prognosis for patients with GISTs.
Topics: Exons; Gastrointestinal Stromal Tumors; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Mutation; Odds Ratio; Prognosis; Proto-Oncogene Proteins c-kit; Receptor, Platelet-Derived Growth Factor alpha; Risk
PubMed: 26349547
DOI: 10.1038/srep13718 -
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 -
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 -
Health Technology Assessment... Oct 2014Bowel cancer is the third most common cancer in the UK. Most bowel cancers are initially treated with surgery, but around 17% spread to the liver. When this happens,... (Review)
Review
BACKGROUND
Bowel cancer is the third most common cancer in the UK. Most bowel cancers are initially treated with surgery, but around 17% spread to the liver. When this happens, sometimes the liver tumour can be treated surgically, or chemotherapy may be used to shrink the tumour to make surgery possible. Kirsten rat sarcoma viral oncogene (KRAS) mutations make some tumours less responsive to treatment with biological therapies such as cetuximab. There are a variety of tests available to detect these mutations. These vary in the specific mutations that they detect, the amount of mutation they detect, the amount of tumour cells needed, the time to give a result, the error rate and cost.
OBJECTIVES
To compare the performance and cost-effectiveness of KRAS mutation tests in differentiating adults with metastatic colorectal cancer whose metastases are confined to the liver and are unresectable and who may benefit from first-line treatment with cetuximab in combination with standard chemotherapy from those who should receive standard chemotherapy alone.
DATA SOURCES
Thirteen databases, including MEDLINE and EMBASE, research registers and conference proceedings were searched to January 2013. Additional data were obtained from an online survey of laboratories participating in the UK National External Quality Assurance Scheme pilot for KRAS mutation testing.
METHODS
A systematic review of the evidence was carried out using standard methods. Randomised controlled trials were assessed for quality using the Cochrane risk of bias tool. Diagnostic accuracy studies were assessed using the QUADAS-2 tool. There were insufficient data for meta-analysis. For accuracy studies we calculated sensitivity and specificity together with 95% confidence intervals (CIs). Survival data were summarised as hazard ratios and tumour response data were summarised as relative risks, with 95% CIs. The health economic analysis considered the long-term costs and quality-adjusted life-years associated with different tests followed by treatment with standard chemotherapy or cetuximab plus standard chemotherapy. The analysis took a 'no comparator' approach, which implies that the cost-effectiveness of each strategy will be presented only compared with the next most cost-effective strategy. The de novo model consisted of a decision tree and Markov model.
RESULTS
The online survey indicated no differences between tests in batch size, turnaround time, number of failed samples or cost. The literature searches identified 7903 references, of which seven publications of five studies were included in the review. Two studies provided data on the accuracy of KRAS mutation testing for predicting response to treatment in patients treated with cetuximab plus standard chemotherapy. Four RCTs provided data on the clinical effectiveness of cetuximab plus standard chemotherapy compared with that of standard chemotherapy in patients with KRAS wild-type tumours. There were no clear differences in the treatment effects reported by different studies, regardless of which KRAS mutation test was used to select patients. In the 'linked evidence' analysis the Therascreen KRAS RGQ PCR Kit (QIAGEN) was more expensive but also more effective than pyrosequencing or direct sequencing, with an incremental cost-effectiveness ratio of £17,019 per quality-adjusted life-year gained. In the 'assumption of equal prognostic value' analysis the total costs associated with the various testing strategies were similar.
LIMITATIONS
The results assume that the differences in outcomes between the trials were solely the result of the different mutation tests used to distinguish between patients; this assumption ignores other factors that might explain this variation.
CONCLUSIONS
There was no strong evidence that any one KRAS mutation test was more effective or cost-effective than any other test.
STUDY REGISTRATION
PROSPERO CRD42013003663.
FUNDING
The National Institute for Health Research Health Technology Assessment programme.
Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Colorectal Neoplasms; Cost-Benefit Analysis; Genetic Techniques; Humans; Liver Neoplasms; Markov Chains; Mutation; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); Quality-Adjusted Life Years; Randomized Controlled Trials as Topic; ras Proteins
PubMed: 25314637
DOI: 10.3310/hta18620 -
Journal of Immunotherapy (Hagerstown,... May 2024The therapeutic landscape for patients with advanced or metastatic non-small cell lung cancer (NSCLC) is rapidly evolving due to advances in molecular testing and the...
Clinical Outcomes of PD-1/PD-L1 Inhibitors Among Patients With Advanced or Metastatic Non-Small Cell Lung Cancer With BRAF, ERBB2/HER2, MET , or RET Alterations: A Systematic Literature Review.
The therapeutic landscape for patients with advanced or metastatic non-small cell lung cancer (NSCLC) is rapidly evolving due to advances in molecular testing and the development of new targeted therapies and immunotherapies. However, the efficacy of programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitors in advanced or metastatic patients with NSCLC whose tumors harbor BRAF V600E mutation, HER2/ERBB2 alteration, MET exon 14 skipping mutation, or RET rearrangement is not completely understood. A systematic literature review was performed to summarize evidence from clinical trials and observational studies on objective response rate, progression-free survival, and overall survival in patients whose tumors express these biomarkers and who were treated with PD-1/PD-L1 inhibitors. Searches of Embase, MEDLINE, conference abstracts, and a clinical trial registry identified a total of 12 unique studies: 4 studies included patients with BRAF V600E mutation, 6 studies included patients with HER2/ERBB2 alteration, 7 studies included patients with MET exon 14 skipping mutation, and 5 studies included patients with RET rearrangement. Across studies, there was heterogeneity in treatment and patient characteristics and a lack of reporting on many important predictive and prognostic factors, including treatment regimens, patients' line of therapy, and tumor PD-L1 expression, which may explain the wide variation in objective response rate, progression-free survival, and overall survival across studies. Therefore, additional studies prospectively evaluating clinical outcomes of PD-1/PD-L1 inhibitors among patients with advanced or metastatic NSCLC whose tumors harbor emerging predictive or prognostic biomarkers are needed to determine whether this class of immunotherapy can provide additional survival benefits for these patients.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Immune Checkpoint Inhibitors; Proto-Oncogene Proteins B-raf; B7-H1 Antigen; Programmed Cell Death 1 Receptor; Proto-Oncogene Proteins c-ret; Receptor, ErbB-2
PubMed: 38112201
DOI: 10.1097/CJI.0000000000000500