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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 -
Frontiers in Oncology 2022Lung adenocarcinoma is a common disease with a high mortality rate. Epidermal growth factor receptor () mutations are found in adenocarcinomas, and oral EGFR-tyrosine...
BACKGROUND
Lung adenocarcinoma is a common disease with a high mortality rate. Epidermal growth factor receptor () mutations are found in adenocarcinomas, and oral EGFR-tyrosine kinase inhibitors (EGFR-TKIs) show good responses. EGFR-TKI therapy eventually results in resistance, with the most common being T790M. T790M is also a biomarker for predicting resistance to first- and second-generation EGFR-TKIs and is sensitive to osimertinib. The prognosis was better for patients with acquired T790M who were treated with osimertinib than for those treated with chemotherapy. Therefore, T790M mutation is important for deciding further treatment and prognosis. Previous studies based on small sample sizes have reported very different T790 mutation rates. We conducted a meta-analysis to evaluate the T790M mutation rate after EGFR-TKI treatment.
METHODS
We systematic reviewed the electronic databases to evaluate the T790M mutation rate after treatment with first-generation (gefitinib, erlotinib, and icotinib) and second-generation (afatinib and dacomitinib) EGFR-TKIs. Random-effects network meta-analysis and single-arm meta-analysis were conducted to estimate the T790M mutation rate of the target EGFR-TKIs.
RESULTS
A total of 518 studies were identified, of which 29 were included. Compared with afatinib, a higher odds ratio (OR) of the T790M mutation rate was observed after erlotinib [OR = 1.48; 95% confidence interval (CI):1.09-2.00] and gefitinib (OR = 1.45; 95% CI: 1.11-1.90) treatments. An even OR of the T790M mutation rate was noted after icotinib treatment (OR = 0.91, 95% CI: 0.46-1.79) compared with that after afatinib. The T790M mutation rate was significantly lower with afatinib (33%) than that with gefitinib (49%) and erlotinib treatments (47%) ( < 0.001). The acquired T790M mutation rate in all participants was slightly lower in Asians (43%) than that in Caucasians (47%).
CONCLUSIONS
Erlotinib and gefitinib had a higher OR for the T790M mutation than afatinib. The T790M mutation rate was significantly lower in afatinib than in gefitinib and erlotinib. T790M is of great significance because osimertinib shows a good prognosis in patients with T790M mutation.
SYSTEMATIC REVIEW REGISTRATION
PROSPERO, identifier CRD42021257824.
PubMed: 35837103
DOI: 10.3389/fonc.2022.869390 -
Journal of Lipid Research Mar 2022Syndromes associated with LCAT deficiency, a rare autosomal recessive condition, include fish-eye disease (FED) and familial LCAT deficiency (FLD). FLD is more severe... (Review)
Review
Syndromes associated with LCAT deficiency, a rare autosomal recessive condition, include fish-eye disease (FED) and familial LCAT deficiency (FLD). FLD is more severe and characterized by early and progressive chronic kidney disease (CKD). No treatment is currently available for FLD, but novel therapeutics are under development. Furthermore, although biomarkers of LCAT deficiency have been identified, their suitability to monitor disease progression and therapeutic efficacy is unclear, as little data exist on the rate of progression of renal disease. Here, we systematically review observational studies of FLD, FED, and heterozygous subjects, which summarize available evidence on the natural history and biomarkers of LCAT deficiency, in order to guide the development of novel therapeutics. We identified 146 FLD and 53 FED patients from 219 publications, showing that both syndromes are characterized by early corneal opacity and markedly reduced HDL-C levels. Proteinuria/hematuria were the first signs of renal impairment in FLD, followed by rapid decline of renal function. Furthermore, LCAT activity toward endogenous substrates and the percentage of circulating esterified cholesterol (EC%) were the best discriminators between these two syndromes. In FLD, higher levels of total, non-HDL, and unesterified cholesterol were associated with severe CKD. We reveal a nonlinear association between LCAT activity and EC% levels, in which subnormal levels of LCAT activity were associated with normal EC%. This review provides the first step toward the identification of disease biomarkers to be used in clinical trials and suggests that restoring LCAT activity to subnormal levels may be sufficient to prevent renal disease progression.
Topics: Humans; Biomarkers; Heterozygote; Lecithin Cholesterol Acyltransferase Deficiency; Mutation; Phosphatidylcholine-Sterol O-Acyltransferase
PubMed: 35065092
DOI: 10.1016/j.jlr.2022.100169 -
Frontiers in Immunology 2023Optimal biomarkers to select patients who will benefit most from immunotherapy remain lacking in nasopharyngeal cancer (NPC). This systematic review and meta-analysis... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Optimal biomarkers to select patients who will benefit most from immunotherapy remain lacking in nasopharyngeal cancer (NPC). This systematic review and meta-analysis aimed to evaluate the association between various biomarkers and clinical outcomes in NPC patients treated with immune checkpoint inhibitors (ICIs).
METHODS
Systematic searches of PubMed, Embase, Cochrane Library, and Web of Science databases were performed up to October 2022. Studies evaluating the association between biomarkers and intended outcomes of ICIs were included. The pooled odds ratio (OR) and hazard ratio (HR) with 95% confidence intervals (CIs) were calculated, respectively, for the objective response rate (ORR) and progression-free survival (PFS) under fixed or random-effect models.
RESULTS
A total of 15 studies involving 1,407 patients were included. The pooled analysis indicated that NPC patients with lower plasma Epstein-Barr virus (EBV) DNA level at baseline (OR = 2.14, 95% CI: 1.46-3.14, < 0.001), decreased EBV DNA load during immunotherapy (OR = 4.57, 95% CI: 2.24-9.34, = 0.002) and higher programmed cell death-ligand 1 (PD-L1) expression (OR = 2.35, 95% CI: 1.36-4.09, = 0.002) had superior ORR than the counterparts. No significant differences of ORR were observed between positive PD-L1 expression and negative PD-L1 expression (OR = 1.50, 95% CI: 0.92-2.45, = 0.104), as well as higher tumor mutation burden (TMB) and lower TMB (OR = 1.62, 95% CI: 0.41-6.44, = 0.494). Patients with lower plasma EBV DNA level at baseline obtained a significant benefit on PFS than those with higher plasma EBV DNA level (HR = 0.52, 95% CI: 0.42-0.63, < 0.001). There were no differences in PFS between decreased EBV DNA load and increased EBV DNA load during immunotherapy (HR = 0.51, 95% CI: 0.22-1.17, = 0.109), higher PD-L1 expression and lower PD-L1 expression (HR = 0.65, 95% CI: 0.42-1.01, = 0.054), positive PD-L1 expression and negative PD-L1 expression (HR = 0.90, 95% CI: 0.64-1.26, = 0.531), lower TMB and higher TMB (HR = 0.84, 95% CI: 0.51-1.38, = 0.684).
CONCLUSION
Lower baseline plasma EBV DNA level, decreased plasma EBV DNA during immunotherapy, and higher PD-L1 expression are reliable biomarkers predicting better response to ICIs treatment. Lower baseline plasma EBV DNA level was also associated with longer PFS. It is warranted to further explore and better illuminate the utility of these biomarkers in future clinical trials and real-world practice.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022324434.
Topics: Humans; Immune Checkpoint Inhibitors; Nasopharyngeal Neoplasms; Epstein-Barr Virus Infections; B7-H1 Antigen; Biomarkers, Tumor; Herpesvirus 4, Human; Nasopharyngeal Carcinoma
PubMed: 37063822
DOI: 10.3389/fimmu.2023.1146898 -
Journal of Personalized Medicine Dec 2021Recently, checkpoint inhibitors have been investigated in metastatic prostate cancer, however their overall effect is unclear and needs to be further investigated. (Review)
Review
UNLABELLED
Recently, checkpoint inhibitors have been investigated in metastatic prostate cancer, however their overall effect is unclear and needs to be further investigated.
OBJECTIVES
The aim of this systematic review is to investigate the oncological response of metastatic castration-resistant prostate cancer patients to immune checkpoint inhibitors.
METHODS
Based on the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement, a systematic review of the literature was conducted through online electronic databases and the American Society of Clinical Oncology (ASCO) Meeting Library. Eligible publications were selected after a staged screening and selection process. RevMan 5.4 software was employed to run the quantitative analysis and forest plots. Risk of bias assessment was conducted using the Cochrane tool and Newcastle-Ottawa Scale for the randomized and non-randomized trials, respectively.
RESULTS
From the 831 results retrieved, 8 studies including 2768 patients were included. There was no significant effect on overall survival (OS) (overall response (OR) = 0.98; Z = 0.42; = 0.67). Meanwhile, progression-free survival (PFS) was significantly better with immune checkpoint inhibitors administration (OR = 0.85; Z = 3.9; < 0.0001). The subgroup analysis for oncological outcomes based on programmed death ligand 1 (PD-L1) positivity status displayed no significant effect, except on prostate-specific antigen response rate (PSA RR) (OR = 3.25; Z = 2.29; = 0.02). Based on DNA damage repair (DDR), positive patients had a significantly better PFS and a trend towards better OS and overall response rate (ORR); the ORR was 40% in positive patients compared to 20% in the negative patients (OR = 2.46; Z = 1.3; = 0.19), while PSA RR was 23.5% compared to 14.3% (OR = 1.88; Z = 0.88; = 0.38). Better PFS was clearly associated with DDR positivity (OR = 0.70; Z = 2.48; = 0.01) with a trend towards better OS in DDR positive patients (OR = 0.71; Z = 1.38; = 0.17). Based on tumor mutation burden (TMB), ORR was 46.7% with high TMB versus 8.8% in patients with low TMB (OR = 11.88; Z = 3.0; = 0.003).
CONCLUSIONS
Checkpoint inhibitors provide modest oncological advantages in metastatic castration-resistant prostate cancer. There are currently no good predictive indicators that indicate a greater response in some patients.
PubMed: 35055323
DOI: 10.3390/jpm12010008 -
Annals of Medicine and Surgery (2012) Jul 2021An emerging infectious zoonosis known as Severe Fever with Thrombocytopenia Syndrome (SFTS) is discovered mainly in Japan, South Korea and China. SFTS virus (SFTSV)... (Review)
Review
BACKGROUND
An emerging infectious zoonosis known as Severe Fever with Thrombocytopenia Syndrome (SFTS) is discovered mainly in Japan, South Korea and China. SFTS virus (SFTSV) which is recently recognised as bunyavirus is borne by ticks such as . It has the capabilities to spread as develop clusters and become a considerable public health threat as this virus could experience rapid evolution via gene mutation. Case fatality rate has been reported up to higher than 30%. The aim of this review is to determine the associated risk factors of SFTS and its outcome.
MATERIALS AND METHODS
Literature search was conducted using online databases PubMed, ScienceDirect, and Scopus. A total of 517 records were identified from searches in PubMed, ScienceDirect, and Scopus. From the final exclusions, a total of 26 studies were included for final analysis.
RESULTS
Associated risk factors to getting SFTS infection include occupation, history of bite from a tick, biological susceptibility, and owning of domestic animal. Fatality rates apart from single case reports range from 15.1% to 50% and are contributed by various factors including delay in hospital admission, high viral load, older age group and presence of comorbid and complication.
CONCLUSION
A seroprevalence study can be conducted amongst the high-risk occupation group such as farmers and agricultural workers, as well as testing cases where viral fever is suspected but available tests for other diseases turns out negative.
PubMed: 34188913
DOI: 10.1016/j.amsu.2021.102501 -
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 -
Gynecologic Oncology Apr 2023The RAS/RAF/MEK/ERK (MAPK) pathway plays a role in ovarian carcinogenesis. Low-grade serous ovarian carcinoma (LGSOC) frequently harbors activating MAPK mutations. MAPK... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The RAS/RAF/MEK/ERK (MAPK) pathway plays a role in ovarian carcinogenesis. Low-grade serous ovarian carcinoma (LGSOC) frequently harbors activating MAPK mutations. MAPK inhibitors have been used in small subsets of ovarian carcinoma (OC) patients to control tumor growth. Therefore, we performed a meta-analysis to evaluate the effectiveness of MAPK inhibitors in OC patients. We aimed to determine the clinical benefit rate (CBR), the subgroup of MAPK inhibitors with the best CBR and overall response rate (ORR), and the most common adverse events.
METHODS
We conducted a search in PubMed, Embase via Ovid, the Cochrane library and clinicaltrials.gov on studies evaluating the efficacy of single MAPK pathway inhibition with MAPK pathway inhibitors in OC patients. Our primary outcome included the CBR, defined by the proportion of patients with stable disease (SD), complete (CR) and partial response (PR). Secondary outcomes included the ORR (including PR and CR) and grade 3 and 4 adverse events. Meta-analysis was performed using a random-effects model.
RESULTS
We included nine studies with a total of 319 OC patients, for which we determined a pooled CBR of 63% (95%-CI 39-84%, I = 92%). Combined treatment with Raf- and MEK inhibitors in in BRAF mutated LGSOC (n = 6) had the greatest efficacy with a CBR of 100% and ORR of 83%. MEK inhibitors had the best efficacy as a single agent. Subgroup analysis by tumor histology demonstrated a significantly higher CBR and ORR in patients with LGSOC, with a pooled CBR and ORR of 87% (95%-CI 81-92%, I = 0%) and 27% (95%-CI 10-48%, I = 77%) respectively. Adverse events of grade 3 or higher were reported frequently: 123 in 167 patients.
CONCLUSIONS
MEK inhibitors are the most promising single agents in (LGS)OC. However, dual MAPK pathway inhibition should be considered in patients with a BRAF mutation, or non-mutated OC with depleted treatment options due indications of higher efficacy and tolerable toxicity profiles.
Topics: Humans; Female; Proto-Oncogene Proteins B-raf; MAP Kinase Signaling System; Signal Transduction; Ovarian Neoplasms; Protein Kinase Inhibitors; Carcinoma, Ovarian Epithelial; Mutation; Mitogen-Activated Protein Kinase Kinases
PubMed: 36841040
DOI: 10.1016/j.ygyno.2023.01.038 -
European Urology Oncology Jun 2024Testing for mutations in Breast Cancer Gene 1/2 (BRCA) has emerged as a novel decision-making tool for clinicians. Patients with metastatic castration-resistant prostate... (Meta-Analysis)
Meta-Analysis Comparative Study Review
Poly (ADP-ribose) Polymerase Inhibitors Have Comparable Efficacy with Platinum Chemotherapy in Patients with BRCA-positive Metastatic Castration-resistant Prostate Cancer. A Systematic Review and Meta-analysis.
CONTEXT
Testing for mutations in Breast Cancer Gene 1/2 (BRCA) has emerged as a novel decision-making tool for clinicians. Patients with metastatic castration-resistant prostate cancer (mCRPC) harboring pathogenic BRCA mutations can benefit from poly (ADP-ribose) polymerase inhibitor (PARPi) and platinum treatments, whereas the impact of the mutation on sensitivity to cabazitaxel and prostate-specific membrane antigen (PSMA)-ligand therapy is currently unknown.
OBJECTIVE
To assess the efficacy of PARPi, platinum, cabazitaxel, and PSMA-ligand therapies in BRCA-positive mCRPC.
EVIDENCE ACQUISITION
Databases were queried in February 2022. We performed data synthesis by using both proportional and individual patient data. For prostate-specific antigen (PSA) response rate (≥50% decrease from baseline [PSA50]) evaluation, we pooled event rates with 95% confidence intervals (CIs). Progression-free (PFS) and overall (OS) survival analyses with individual patient data were performed with the mixed-effect Cox proportional hazard model and single-arm random-effect analysis, providing pooled medians.
EVIDENCE SYNTHESIS
We included 23 eligible studies with 901 BRCA-positive mCRPC patients. PSA50 response rates for PARPi and platinum were 69% (CI: 53-82%), and 74% (CI: 49-90%), respectively. Analyses of OS data showed no difference between PARPi and platinum treatments (hazard ratio: 0.86; CI: 0.49-1.52; p = 0.6). The single-arm OS and PFS analyses revealed similarities among different PARPis; pooled PFS and OS medians were 9.7 mo (CI: 8.1-12.5) and 17.4 mo (CI: 12.7-20.1), respectively.
CONCLUSIONS
Our data revealed that different PARPis were similarly effective in terms of PFS and OS. Moreover, we found that PARPi and platinum therapy were comparable in terms of PSA50 response rate and OS, highlighting that platinum is a valid treatment option for BRCA-positive mCRPC patients. However, prospective interventional studies comparing these agents are essential to provide a higher level of evidence.
PATIENT SUMMARY
In this report, we found that different poly (ADP-ribose) polymerase inhibitors had similar efficacy, and platinum was a valid treatment option in BRCA-positive metastatic castration-resistant prostate cancer patients.
Topics: Humans; Prostatic Neoplasms, Castration-Resistant; Poly(ADP-ribose) Polymerase Inhibitors; Male; Treatment Outcome; BRCA2 Protein; Antineoplastic Agents; Neoplasm Metastasis; BRCA1 Protein
PubMed: 37722977
DOI: 10.1016/j.euo.2023.09.001 -
Research and Practice in Thrombosis and... Oct 2019Portal vein thrombosis (PVT) is common in cirrhosis. PVT is associated with high morbidity and mortality. Individual reports suggest that PVT occurs more frequently in...
BACKGROUND
Portal vein thrombosis (PVT) is common in cirrhosis. PVT is associated with high morbidity and mortality. Individual reports suggest that PVT occurs more frequently in patients with cirrhosis and inherited thrombophilia. The relationship between cirrhosis, PVT development, and inherited thrombophilia was explored in this study. The aim of the study was to determine whether cirrhotic patients with nontumoral PVT have an increased rate of inherited thrombophilia.
METHODS
Studies were identified by searching electronic databases up to October 2017 with English language and human subject restrictions. Two independent reviewers screened citations and extracted data. Magnitude of effect was calculated to obtain aggregate estimates of effect size and 95% confidence intervals (CIs). Between-study variability and heterogeneity were assessed.
RESULTS
Of 2893 citations identified, 9 studies composed of 1929 subjects with cirrhosis were included. The overall prevalence of PVT was 6.5% (n = 125). Both prothrombin G20210A mutation (odds ratio [OR], 2.43; 95% CI, 1.07-5.53; = 0.03) and factor V Leiden (FVL) (OR, 1.98; 95% CI, 1.06-3.68; = 0.03) were significantly associated with PVT risk. Methyltetrahydrofolate reductase C677T mutation was not associated with increased PVT risk. No heterogeneity or publication bias was observed. One important study with opposite findings could not be included due to lack of primary data.
CONCLUSIONS
FVL and PTG20210A mutation were associated with increased PVT risk in patients with cirrhosis. This finding reframes the role of inherited thrombophilia in PVT development in patients with cirrhosis. Future prospective studies investigating screening for inherited thrombophilia in all cirrhosis patients with PVT seem warranted.
PubMed: 31624785
DOI: 10.1002/rth2.12253