-
Annals of Translational Medicine May 2022Non-small cell lung cancer (NSCLC) is the most common subtype of all lung cancers, and KRAS is the most common mutation in this population. Unfortunately, this subgroup...
BACKGROUND
Non-small cell lung cancer (NSCLC) is the most common subtype of all lung cancers, and KRAS is the most common mutation in this population. Unfortunately, this subgroup remains "undruggable" with the lack of an approved targeted therapy. Selumetinib has been investigated as a secondary therapy in several trials and compared to various drug regimens. Therefore, we conducted this systematic review and network meta-analysis to determine the comparative effectiveness of this drug as compared to others in patients with late-stage and malignant NSCLC.
METHODS
Up to July 1, 2020, 9 databases (PubMed, Scopus, Web of Science, mRCT, ICTRP, clinicaltrials.gov, VHL, SIGLE, and Google Scholar) were searched for studies following the PICOS framework: randomized trials reporting the efficacy (rate of disease progression/lack of response) of selumetinib compared to other therapies in patients with late-stage/metastatic NSCLC. The quality of retrieved studies were assessed with the revised Cochrane risk-of-bias tool. Frequentist network meta-analysis was conducted to estimate the efficacy of selumetinib as compared to other therapies and/or placebo.
RESULTS
Out of the 163 articles yielded from the primary search, 9 studies (1,195 patients) were finally included in our systematic review. The majority of clinical cases had a performance status (PS) of 0-2, and the mean age was 62 years. The overall efficacy of selumetinib was 71.77% (95% CI: 63.24-81.45%), with selumetinib administered alone having better efficacy compared to combined therapy (65.20% 74.08%). In the network analysis, selumetinib had higher efficacy compared to chemo- or immune therapy, but not significantly so. The overall SAE rate of selumetinib was 42.96% (95% CI: 34.74-53.13%), with selumetinib having a significantly better safety profile compared to combined therapy (10.49% 47.38%). In the network analysis, the placebo had the best safety profile followed by selumetinib and chemo- and immune therapy. Five studies had high risk of bias, 2 had some concerns, and 2 had low risk of bias.
DISCUSSION
The efficacy of selumetinib is not superior compared to combined therapy for treating NSCLC but does have a better safety profile. Current evidence is still limited, and more robust trials are still required.
PubMed: 35722363
DOI: 10.21037/atm-22-1849 -
Therapeutic Advances in Hematology 2021DDX41 serves as a DNA sensor in innate immunity and mutated is pathogenic, mainly for myeloid neoplasms. (Review)
Review
BACKGROUND
DDX41 serves as a DNA sensor in innate immunity and mutated is pathogenic, mainly for myeloid neoplasms.
METHODS
In this study, "" was searched in and between 1 January 2015 and 29 April 2021 with individual-patient data seeking. A meta-analysis was not valid here due to the absence of a large dataset. Thirty articles were finally included in the qualitative analysis and 277 patients from 20 studies without overlap were involved in the quantitative summary.
RESULTS
Pooled incidence was 3.3% (95% confidence interval 2.4-4.2%) of unselected myeloid neoplasms. Patients with hematologic disorders harboring mutated were featured as 80% males, median 66 (20-88) years old at diagnosis, 75% acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS), 64% with normal karyotype. Eighty-five percent of patients had germline variants which were nationally diverse and more of frameshift type, whereas 64% of patients had somatic variants where p.R525H and missense dominated. and were the top frequent concomitant somatic mutations. Therapeutically, 70% overall response rate was obtained of hypomethylating agents in MDS, 96% complete remission of chemotherapy in AML, and 8% of relapse in hematopoietic stem cell transplant. Neither overall survival nor progression-free survival could be summed.
CONCLUSIONS
Several significant clinical differences were observed in different diagnosis groups, familial and sporadic cases, and p.R525H compared with other somatic variants. In conclusion, myeloid neoplasms carrying mutations were mainly older, male, MDS, and AML patients who had promising responses to treatment. Both germline and somatic variants possessed unique characteristics and groups of interest presented certain differences worth further research. (CRD42021228886).
PubMed: 34349893
DOI: 10.1177/20406207211032433 -
Cureus Sep 2020Gastric cancer is the third-most fatal cancer in the world. Though over the years, we saw patients mostly with intestinal type accounting for the highest mortality... (Review)
Review
Gastric cancer is the third-most fatal cancer in the world. Though over the years, we saw patients mostly with intestinal type accounting for the highest mortality rate, the recent rise of the diffuse form with germline E-cadherin (CDH1) mutations has added a whole new level of interest to study in detail about the association between CDH1 and diffuse gastric cancer (DGC). This introduced a set guideline formulated by Internal Gastric Cancer Linkage Consortium (IGCLC) for patients with family history of diffuse gastric cancer and invasive lobular breast cancer (ILBC). The analysis of this link was also important to set proper management protocol for patients who were CDH1 mutation carriers which now involves genetic counselling, endoscopic surveillance and screening and prophylactic total gastrectomy (PTG). The study was conducted in accordance to the 'PRISMA guidelines for reporting systematic review and meta-analysis'. Peer-reviewed studies were included from the PubMed database and relevant articles were selected to be included in the study. Appropriate inclusion/exclusion criteria with free full text English articles were applied while selecting the articles. A total of 10 studies on review with different study populations showed that of the 42 patients who were diagnosed with diffuse gastric cancer, 88% of them showed a positive germline E-cadherin gene mutation and 100% of the CDH1 mutation carriers showed microscopic changes of signet ring cell adenocarcinoma of the stomach. The beneficial effects of PTG with better survival rates and low mortality rates has outweighed other treatment modalities. Laparoscopic approach has proved to be more useful and a safer approach for gastrectomy surgeries with better post-operative management. The need for prophylactic mastectomy is also increased in the recent times and thus this requires a new set of guidelines for ILBC patients with hereditary diffuse gastric cancer (HDGC) syndrome.
PubMed: 33062523
DOI: 10.7759/cureus.10406 -
Lung Cancer (Amsterdam, Netherlands) May 2023Enteric-type adenocarcinoma of the lung (lung-ETAC, former pulmonary enteric adenocarcinoma, PEAC) is a rare subtype of non-small cell lung cancer (NSCLC), which shares... (Meta-Analysis)
Meta-Analysis Review
Enteric-type adenocarcinoma of the lung (lung-ETAC, former pulmonary enteric adenocarcinoma, PEAC) is a rare subtype of non-small cell lung cancer (NSCLC), which shares morphological and immunohistochemical features with lung and colorectal adenocarcinoma. Few data are available on patient prognosis, possible prognostic factors and systemic approach to metastatic disease. We performed a pooled analysis and a systematic review of published lung-ETAC, along with an additional case description. Thirty-one eligible publications were identified, providing data from 126 patients. In the 127 patients overall analyzed, median overall survival (OS) was 56.0 (range 36.7-75.3) months in early-stage patients and 14.0 (range 4.5-23.5) months in those with advanced/metastatic disease. Median disease-free survival (DFS) after radical surgery was 24 (range 22.6-35.1) months. Smoking status (HR 4.304, 95% CI: 1.261-14.693, p = 0.020) and node involvement (HR 1.853, 95% CI: 1.179-2.911, p = 0.007) were the negative independent prognostic factors at multivariate analysis. As regards systemic therapies for advanced cases, no firm conclusions were drawn about the efficacy of lung cancer-oriented chemotherapy regimens as opposed to colon cancer-oriented ones. Molecular analysis of lung-ETAC revealed a relatively high mutational rate, with alterations in several druggable molecular pathways, KRAS and NRAS (31%) were the most frequently mutated oncogenes, followed by ROS1 (15%), RET (13%), BRAF (11%), EGFR (8%) and ALK (6%). Moreover, 3 (15%) out of 20 cases showed DNA mismatch repair deficiency (dMMR). In conclusion, advanced lung-ETAC patients appeared to have a better prognosis compared to other subtypes of NSCLC. Moreover, the mutational rate and microsatellite instability found in lung-ETACs suggest that a significant proportion of these patients could benefit from target therapies and immunotherapy.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Protein-Tyrosine Kinases; Mutation; Proto-Oncogene Proteins; Adenocarcinoma; Adenocarcinoma of Lung; Prognosis; Lung
PubMed: 37015149
DOI: 10.1016/j.lungcan.2023.107176 -
Frontiers in Cardiovascular Medicine 2022Mutations in the gene-encoding for the major Ca channel of the heart-may exhibit a variety of clinical manifestations. These include typical or atypical Timothy...
Geno- and phenotypic characteristics and clinical outcomes of gene mutation associated Timothy syndrome, "cardiac only" Timothy syndrome and isolated long QT syndrome 8: A systematic review.
BACKGROUND
Mutations in the gene-encoding for the major Ca channel of the heart-may exhibit a variety of clinical manifestations. These include typical or atypical Timothy syndromes (TS) which are associated with multiple organ manifestations, and cardiac involvement in form of malignant arrhythmias, QTc prolongation, or AV block. "Cardiac only" Timothy syndrome (COTS) shows no extracardiac manifestation, whereas some gene mutations are associated with QTc prolongation alone (isolated long QT syndrome 8, LQT8).
METHODS
A systematic search of the literature reporting cases of gene mutation associated syndromes, including TS, COTS and isolated LQT8 major databases published from 2004 through 2019 was performed. Detailed patient-level phenotypic and genotypic characteristics, as well as long-term outcome measures were collected and compared between pre-specified patient groups, defined both on phenotype and genotype.
RESULTS
A total of 59 TS, 6 COTS, and 20 isolated LQT8 index cases were identified. Apart of syndactyly or baldness, there were no major differences regarding clinical manifestations or outcome measures between TS subtypes, either defining TS subtypes on the genotype or based on the phenotype. Both subtypes were characterized by an extreme degree of QTc prolongation (median ≥600 ms) which were reflected in high major adverse cardiac event rate. On the other hand, there were marked differences between TS, COTS, and isolated LQT8. Timothy syndrome was characterized by a much earlier disease onset, much more pronounced QTc prolongation and much higher mortality rate than COTS or isolated LQT8. Similar differences were observed comparing exon 8/8A vs. non-exon 8/8A mutation carriers. TS showed a high degree of genetic homogeneity, as the p.Gly406Arg mutation either in exon 8 or exon 8A alone was responsible for 70% of the cases.
CONCLUSIONS
Clinical phenotypes associated with mutations in the gene show important clinical differences. Timothy syndrome is associated with the most severe clinical phenotype and with the highest risk of morbidity and mortality. However, distinguishing TS subtypes, in any form, are not supported by our data.
SYSTEMATIC REVIEW REGISTRATION
[https://www.crd.york.ac.uk/prospero/], identifier [CRD42020184737].
PubMed: 36523353
DOI: 10.3389/fcvm.2022.1021009 -
Frontiers in Oncology 2021Poly (ADP-ribose) polymerase (PARP) inhibitors have shown promising results in metastatic triple-negative breast cancers (TNBCs). We therefore performed a systematic...
PURPOSE
Poly (ADP-ribose) polymerase (PARP) inhibitors have shown promising results in metastatic triple-negative breast cancers (TNBCs). We therefore performed a systematic review and meta-analysis to evaluate the efficacy and safety of this drug in patients with advanced or metastatic TNBC.
METHODS
A systematic literature search of PubMed, Embase, Scopus, Web of Science, and Cochrane Central Register of Controlled Trials for synonyms of "PARP inhibitors" and "breast cancer" was carried out. All published phase II/III clinical studies of PARP inhibitors in patients with advanced/metastatic TNBC were screened. Data were extracted independently by two authors and analyzed using Review Manager software version 5.3. End points include overall response rate (ORR), progression-free survival (PFS), and adverse events.
RESULTS
Ten clinical trials were identified, with a total of 1,495 patients included. Pooled analyses showed that PARP inhibitors could provide a significant improvement of ORR [risk ratio (RR) = 2.00; 95% confidence interval (CI), 1.14-3.50; p = 0.02) and PFS [hazard ratio (HR) = 0.68; 95%Cl, 0.59-0.77; p < 0.0001) compared to chemotherapy in the whole population. In subgroup analysis, patients with mutation had a higher objective response to PARP inhibitor, with an RR of 2.85 (95%CI, 1.34-6.06; p = 0.007) compared to wild-type patients. However, no significant difference in ORR was observed between the homologous recombination deficiency (HRD) positive and non-HRD subgroups (RR = 1.82; 95%CI, 0.81-4.08; p = 0.14). Hematological toxicity is a common adverse event of PARP inhibitors.
CONCLUSIONS
PARP inhibitors are effective options for the treatment of patients with advanced or metastatic TNBC. Compared with patients without germline mutation, patients with germline mutation could benefit more from PARP inhibitors. In clinical setting, hematological toxicity associated with PARP inhibitors should be monitored regularly.
PubMed: 34778059
DOI: 10.3389/fonc.2021.742139 -
Oncotarget Jul 2017Since it is impossible to recognize malignancy at fine needle aspiration (FNA) cytology in indeterminate thyroid nodules, surgery is recommended for all of them.... (Meta-Analysis)
Meta-Analysis Review
Since it is impossible to recognize malignancy at fine needle aspiration (FNA) cytology in indeterminate thyroid nodules, surgery is recommended for all of them. However, cancer rate at final histology is <30%. Many different test-methods have been proposed to increase diagnostic accuracy in such lesions, including Galectin-3-ICC (GAL-3-ICC), BRAF mutation analysis (BRAF), Gene Expression Classifier (GEC) alone and GEC+BRAF, mutation/fusion (M/F) panel, alone, M/F panel+miRNA GEC, and M/F panel by next generation sequencing (NGS), FDG-PET/CT, MIBI-Scan and TSHR mRNA blood assay.We performed systematic reviews and meta-analyses to compare their features, feasibility, diagnostic performance and cost. GEC, GEC+BRAF, M/F panel+miRNA GEC and M/F panel by NGS were the best in ruling-out malignancy (sensitivity = 90%, 89%, 89% and 90% respectively). BRAF and M/F panel alone and by NGS were the best in ruling-in malignancy (specificity = 100%, 93% and 93%). The M/F by NGS showed the highest accuracy (92%) and BRAF the highest diagnostic odds ratio (DOR) (247). GAL-3-ICC performed well as rule-out (sensitivity = 83%) and rule-in test (specificity = 85%), with good accuracy (84%) and high DOR (27) and is one of the cheapest (113 USD) and easiest one to be performed in different clinical settings.In conclusion, the more accurate molecular-based test-methods are still expensive and restricted to few, highly specialized and centralized laboratories. GAL-3-ICC, although limited by some false negatives, represents the most suitable screening test-method to be applied on a large-scale basis in the diagnostic algorithm of indeterminate thyroid lesions.
Topics: Algorithms; Biomarkers, Tumor; Cost-Benefit Analysis; Cytodiagnosis; Disease Management; Humans; Molecular Diagnostic Techniques; Reproducibility of Results; Sensitivity and Specificity; Thyroid Neoplasms; Thyroid Nodule
PubMed: 28472764
DOI: 10.18632/oncotarget.17220 -
Clinical Kidney Journal Apr 2016Advanced melanoma has been traditionally unresponsive to standard chemotherapy agents and used to have a dismal prognosis. Genetically targeted small-molecule inhibitors... (Review)
Review
Advanced melanoma has been traditionally unresponsive to standard chemotherapy agents and used to have a dismal prognosis. Genetically targeted small-molecule inhibitors of the oncogenic BRAF V600 mutation or a downstream signaling partner (MEK mitogen-activated protein kinase) are effective treatment options for the 40-50% of melanomas that harbor mutations in BRAF. Selective BRAF and MEK inhibitors induce frequent and dramatic objective responses and markedly improve survival compared with cytotoxic chemotherapy. In the past decade after discovery of this mutation, drugs such as vemurafenib and dabrafenib have been approved by the US Food and Drug Administration (FDA) and the European Medicines Agency for the treatment of V600-mutated melanomas. While the initial trials did not signal any renal toxicities with the BRAF inhibitors, recent case reports, case series and FDA adverse reporting systems have uncovered significant nephrotoxicities with these agents. In this article, we systematically review the nephrotoxicities of these agents. Based on recently published data, it appears that there are lower rates of kidney disease and cutaneous lesions seen with dabrafenib compared with vemurafenib. The pathology reported in the few kidney biopsies done so far are suggestive of tubulo interstitial damage with an acute and chronic component. Electrolyte disorders such as hypokalemia, hyponatremia and hypophosphatemia have been reported as well. Routine monitoring of serum creatinine and electrolytes and calculation of glomerular filtration rate prior to the first administration when treating with dabrafenib and vemurafenib are essential.
PubMed: 26985376
DOI: 10.1093/ckj/sfv149 -
Frontiers in Oncology 2021The aim of this meta-analysis was to evaluate efficacy and toxicity of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) in combination with...
First-Generation EGFR-TKI Plus Chemotherapy Versus EGFR-TKI Alone as First-Line Treatment in Advanced NSCLC With EGFR Activating Mutation: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.
OBJECTIVE
The aim of this meta-analysis was to evaluate efficacy and toxicity of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) in combination with chemotherapy (CT) compared to EGFR-TKI monotherapy as first-line treatment in advanced non-small cell lung cancer (NSCLC) harboring activating EGFR mutation.
METHODS
A systematic literature search of randomized controlled trials using Cochrane Library, PubMed, Embase, and Web of Science, was performed up to Jan. 7th, 2020. Hazard ratios (HRs) with 95% confidence intervals (CI) were calculated as effect values for progress-free survival (PFS) and overall survival (OS). Risk ratio (RR) and Odds ratio (OR) were calculated as effect values for objective response rate (ORR) and toxicity, respectively.
RESULTS
A total of eight randomized trials involving 1,349 advanced NSCLC patients with sensitive EGFR mutation were included in the meta-analysis. All patients in both groups received first-generation TKI as first-line treatment. The pooled HR of PFS and OS was 0.56 (95% CI = 0.50-0.64; P <0.00001) and 0.70 (95% CI = 0.54-0.90; P = 0.005), respectively. Subgroup analysis showed significantly higher OS advantages in patients receiving doublet CT (P = 0.02) and concurrent therapy (P = 0.002). The ORR in the EGFR-TKI plus CT group was significantly higher than in the EGFR-TKI monotherapy group (RR = 1.18, 95% CI = 1.10-1.26). The combination regimen showed a higher incidence of chemotherapy-induced toxicities. Subgroup analysis indicated that doublet chemotherapy rather than single-agent chemotherapy significantly increased incidence of grade 3 or higher leukopenia, neutropenia and anemia.
CONCLUSIONS
Compared with EGFR-TKI monotherapy, the combination of first-generation EGFR-TKI and CT, especially when applying concurrent delivery of platinum-based doublet chemotherapeutic drugs, significantly improve ORR and prolong PFS and OS in first-line treatment for advanced EGFR-mutated NSCLC. Although increasing incidence of chemotherapy-induced toxicities occurs in the combination group, it is well tolerated and clinically manageable.
PubMed: 33928022
DOI: 10.3389/fonc.2021.598265 -
Critical Reviews in Oncology/hematology Apr 2024We conducted a systematic review and meta-analysis to evaluate outcomes after allogeneic hematopoietic stem cell transplantation (Allo-HSCT) in TP53-mutated... (Meta-Analysis)
Meta-Analysis Review
We conducted a systematic review and meta-analysis to evaluate outcomes after allogeneic hematopoietic stem cell transplantation (Allo-HSCT) in TP53-mutated myelodysplastic syndromes (MDS). A literature search was performed on PubMed, Cochrane, Embase, and Clinicaltrials.gov. After screening 626 articles, eight studies were included. Data were extracted following the PRISMA guidelines and analyzed using the meta-package by Schwarzer et al. We analyzed 540 patients. The pooled median 3 (1-5) year overall survival was 21% (95% CI 0.08-0.37, I2=91%, n=540). The pooled relapse rate was 58.9% (95% CI 0.38-0.77, I2=93%, n=487) at a median of 1.75 (1-3) years. The pooled 4-year progression- free survival was 34.8% (95% CI 0.15-0.57, I2=72%, n=105). Outcomes of Allo-HSCT for TP53-mutated MDS patients remain poor, with 21% OS at three years; however, Allo-HSCT confers a survival advantage as compared to non-transplant palliative therapies. Our findings suggest the need to explore novel therapeutic agents in prospective clinical trials.
Topics: Humans; Prospective Studies; Myelodysplastic Syndromes; Hematopoietic Stem Cell Transplantation; Progression-Free Survival; Transplantation Conditioning; Tumor Suppressor Protein p53
PubMed: 38423375
DOI: 10.1016/j.critrevonc.2024.104310