Search Results (67)

The objective of this study was to evaluate the effect of tyrosine on behavior and ruminal meta-taxonomic profile of Altay sheep. Twelve rams with the lowest behavioral responses to humans and twelve rams with the highest behavioral responses were sorted into calm and nervous groups, respectively. Following the 2 × 2 factorial design, the rams from each group were equally assigned two treatments of a basal diet and a diet with an extra 4 g of tyrosine for 30 d. The temperament trait, growth performance, rumen fermentation parameters, ruminal epithelium antioxidant capacity, and rumen microbial composition were measured at the end of the feeding experiment. The results showed that tyrosine treatment led to a decreased number of crosses in the arena test in nervous sheep (p < 0.05). The tyrosine treatment led to increased antioxidant markers in the rumen epithelium, such as catalase, total antioxidant capacity, and GSH content in rumen epithelial tissues (p < 0.05) in calm and nervous sheep. The total volatile fatty acids and propionic acid content in the rumen were increased by tyrosine treatment in nervous and calm sheep (p < 0.05). The rumen microbial study revealed that the dominant microbial genera were Cryptobacteroides, Prevotella, Limivicinus, Quinella, UBA1711, RUG740, Sachharofermentans, Limomorpha, Soladiphilus, Flexinia, and others in both the tyrosine treatment and temperament groups. A combined effect of treatment and temperament was seen on the abundance of two microbial genera, UBA1711 and RUG740 (p < 0.05). These findings suggest that tyrosine-treated Altay sheep would experience less stress during production, resulting in reduced oxidative stress in the rumen epithelium and improved propionic acid production in the rumen compared with that of basal-diet-treated Altay sheep. Meanwhile, the effect of the dietary tyrosine treatment on ruminal microbial diversity was lower, suggesting lesser degradation of tyrosine by ruminal microbes in Altay sheep. Full article

Programmed Death-Ligand 1 (PD-L1) is a major target for immunotherapy using checkpoint inhibitors (CPIs), particularly in lung cancer treatment. Tumoral PD-L1 expression has been recognized as a natural predictor of CPI response. This predictive relationship is primarily due to its upregulation by interferon-gamma, which is released by immune cells (mainly T lymphocytes and natural killer cells) in proximity to tumor cells, driving an immune resistance mechanism. However, PD-L1 expression is modulated at multiple levels, including oncogenic signaling pathways, and transcriptional and post-transcriptional regulations, potentially leading to false positive predictions. Conversely, variable glycosylation of PD-L1 may compromise the accuracy of immunohistochemical measurements, resulting in false negative predictive data. In addition, PD-L1 expression demonstrates relative instability throughout treatment courses (e.g., chemotherapy and tyrosine kinase inhibitors), further limiting its clinical utility. In this review, we focused on the molecular mechanisms governing PD-L1 expression with a special emphasis on lung cancer. We also discussed biomarker strategies for optimizing patient selection for checkpoint inhibitor therapy where multimodal/multi-omics meta-biomarker approaches are emerging. Such comprehensive PD-L1-enriched biomarker strategies require evaluation through large-scale prospective studies, particularly in lung cancer, where numerous competing predictive candidates exist for CPI response. Full article

Background: Transarterial chemoembolization (TACE) is the standard treatment for patients with intermediate-stage hepatocellular carcinoma (HCC); however, its survival benefits remain unsatisfactory. In this systematic review, we aimed to compare the clinical outcomes of tyrosine kinase inhibitors (TKIs) combined with TACE and TACE alone in patients with intermediate-stage HCC. Methods: A systematic review and meta-analysis were conducted following the Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines. Randomized controlled trials (RCTs) comparing TACE plus TKIs with TACE alone in patients with HCC were retrieved from PubMed, Embase, and the Cochrane Library. The primary outcomes included overall survival (OS) and progression-free survival (PFS), reported as hazard ratios (HRs) with 95% confidence intervals (CIs). Secondary outcomes included the overall response rate (ORR) and disease control rate (DCR), which were analyzed using risk ratios (RRs). Heterogeneity was assessed using the I² statistic. Results: Fourteen RCTs were included in this meta-analysis. Compared to TACE alone, TACE plus TKIs significantly improved PFS (HR = 0.74, 95% CI: 0.59–0.93, p = 0.01, I² = 87%) and the ORR (RR = 1.29, 95% CI: 1.11–1.51, p = 0.001), but not OS (HR = 0.84, 95% CI: 0.69–1.03, p = 0.10, I² = 65%) and the DCR (RR = 1.05, 95% CI: 0.99–1.11, p = 0.08). Subgroup analysis showed that TACE plus TKIs significantly increased OS in patients with hepatitis B virus (HBV) infection (HR = 0.67, 95% CI: 0.51–0.88), but not in those with hepatitis C virus (HCV) infection or those without HBV and HCV infection. Moreover, patients with HBV infection, male patients, and those with a good functional status (ECOG performance status of 0) had better PFS than others. Conclusions: Compared with TACE alone, TACE combined with TKIs can significantly improve PFS and the ORR in patients with intermediate-stage HCC. Furthermore, combination treatment can significantly improve OS in patients with HBV infection, but not in patients with HCV infection. Further research is required to optimize patient selection and treatment strategies. Full article

Non-small cell lung cancer (NSCLC) accounts for 85% of lung cancer cases globally and most patients receive their diagnosis at advanced or metastatic disease stages. The use of tyrosine kinase inhibitors (TKIs) such as erlotinib (first-generation) and osimertinib (third-generation) to treat NSCLC is possible because of activating mutations in the epidermal growth factor receptor (EGFR). Although osimertinib has shown better results in recent trials, direct and updated comparisons with erlotinib, especially in combination regimens, are still limited. Background/Objectives: This study aimed to compare the efficacy and safety of osimertinib versus erlotinib, both as monotherapies and in combination, in treatment-naïve patients with advanced or metastatic EGFR-mutated NSCLC. Methods: A systematic review and network meta-analysis were conducted following PRISMA-NMA guidelines and registered in PROSPERO (CRD42025649761). PubMed, EMBASE, and Scopus were searched up to February 2025 for randomized controlled trials (RCTs) that compared erlotinib- or osimertinib-based regimens in previously untreated EGFR-mutated advanced NSCLC. Outcomes included overall survival (OS), progression-free survival (PFS), and grade ≥ 3 adverse events. A frequentist random-effects model was used, and treatments were ranked using p-scores. Results: Eleven RCTs (2341 patients) were included. Osimertinib, alone or with chemotherapy, resulted in significantly longer OS compared to erlotinib-based regimens (HR for OS vs. erlotinib: 1.59, 95% CI 1.09–2.31). All osimertinib and erlotinib regimens outperformed chemotherapy for PFS, but no statistically significant differences were observed between osimertinib and erlotinib. Severe adverse events were comparable, though osimertinib ranked highest for safety. The combination of osimertinib with chemotherapy achieved the highest p-scores for both OS and PFS. Conclusions: Osimertinib is associated with superior overall survival and comparable safety versus erlotinib-based strategies in first-line treatment of advanced EGFR-mutated NSCLC. These findings reinforce osimertinib as the preferred first-line option in this setting. Full article

Background/Objectives: Anlotinib is a novel oral antiangiogenic tyrosine kinase inhibitor (TKI) approved as a third-line treatment for advanced non-small-cell lung cancer (NSCLC). However, its efficacy in combination with docetaxel remains incompletely understood. Given the need for effective second-line therapies after platinum-based chemotherapy, this systematic review aims to evaluate the therapeutic potential of anlotinib plus docetaxel in advanced NSCLC. Methods: The PubMed, WOS, Medline, and Scopus databases were screened for published articles up to 12 April 2024. We included RCTs comparing anlotinib plus docetaxel with docetaxel alone in advanced NSCLC after receiving platinum-based chemotherapy, reporting progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR) as outcomes for both groups. Results: Our systematic review included three randomized controlled trials (RCTs) with a total of 151 patients in the anlotinib plus docetaxel group and 132 in the docetaxel-only group. Meta-analysis results demonstrated that the combination therapy significantly prolonged PFS (mean difference (MD) = 2.98, 95% confidence interval (CI), 1.95–4.00; p < 0.00001) and improved ORR (risk ratio (RR) = 3.04, 95% CI = 1.77–5.24; p < 0.00001). Additionally, the DCR was notably higher in the combination group (RR = 1.58, 95% CI = 1.34–1.87; p < 0.00001). Conclusions: Anlotinib plus docetaxel appears to be more effective as a second-line treatment of advanced NSCLC than docetaxel in prolonging PFS and increasing ORR and DCR. Full article

Background/Objectives: To study whether shorter restaging intervals are associated with lower hazard ratios (HRs) for progression-free survival (PFS), as suggested in breast cancer. Methods: Studies supporting the registration of oncologic drugs in Switzerland from 2010 to 2022 were analyzed. HRs and 95% confidence intervals (CIs) for PFS were pooled in a meta-analysis using the generic inverse-variance method and a random-effects model in RevMan v5.4. The HRs were stratified by restaging intervals (<median vs. ≥median), both overall and within prespecified subgroups. Results: A total of 112 studies comprising 69,579 patients were included. The median restaging interval was 8 weeks, with a range of 4 to 18 weeks. Longer restaging intervals (≥8 weeks) were associated with lower HRs compared to shorter intervals (<8 weeks), with pooled HRs of 0.48 (95% CI: 0.44–0.52) and 0.58 (95% CI: 0.53–0.63), respectively. The difference between the groups was statistically significant (p = 0.005), with a substantial heterogeneity (Cochran’s Q p < 0.001; I² = 90%). Subgroup analyses based on treatment type, including immunotherapy, monoclonal antibodies, and tyrosine kinase inhibitors, did not show any statistically significant differences in HRs. Studies of melanoma with shorter staging intervals were associated with lower HRs (0.44 vs. 0.58, p = 0.02), whereas shorter interval studies of kidney cancer had higher HRs (0.67 vs. 0.44, p = 0.01). Sensitivity analyses with other cut-offs and a meta-regression yielded similar results. Conclusions: Studies leading to the authorization of drugs to treat incurable solid tumors applying restaging intervals ≥ 8 weeks were associated with lower HRs for PFS. The potential impact of restaging intervals on the results for PFS warrants further investigation. Full article

Monoterpenes (MTs) are plants’ secondary metabolites and major components of essential oils (EOs), widely used in the pharmaceutical industry. However, its neuroprotective effects, particularly in Parkinson’s disease (PD) have not been fully demonstrated. PD is a progressive neurological disorder marked by dopaminergic neuron loss in the substantia nigra, motor symptoms being the most reported ones. This review evaluates the evidence supporting the use of MTs as potential neuroprotective agents. PubMed, SCOPUS, Google Scholar, and ScienceDirect databases were searched for articles on MTs in murine models with any type of administration. The PRISMA guidelines were followed. After screening 405 records, 32 were included in the systematic review and 30 were included in the meta-analysis. Fifteen MTs, commonly found in EOs, were identified as potential therapeutic agents for PD. The meta-analysis revealed that MTs administration improved motor performance, increased tyrosine hydroxylase levels, reduced oxidative stress markers (malondialdehyde) and proinflammatory cytokines (IL-6, IL-1, TNF-α), and enhanced antioxidant enzymes (catalase, superoxide dismutase) in parkinsonian animals. The antioxidant and anti-inflammatory properties of MTs appear to be key mechanisms in mitigating dopaminergic neurodegeneration. However, further clinical research is essential to translate these findings into practical applications. Full article

Deucravacitinib, a selective oral tyrosine kinase 2 (TYK2) inhibitor, has demonstrated strong efficacy in the treatment of moderate-to-severe psoriasis. It works through an allosteric mechanism to selectively inhibit TYK2, leading to the suppression of the IL-23/Th17/IL-17 axis and a reduction in key pro-inflammatory cytokines such as IL-17A, IL-17F, IL-22, and IL-23. This review focuses on the clinical implications of deucravacitinib in East Asian patients, highlighting its efficacy, safety, and differences in treatment outcomes compared to other populations. Data from pivotal trials such as POETYK PSO-3 and PSO-4, which included East Asian populations, demonstrated robust efficacy and safety profiles, often surpassing results observed in global trials like POETYK PSO-1 and PSO-2. Subgroup analyses and network meta-analyses further corroborate these findings, providing a comprehensive understanding of its therapeutic potential in this demographic. Factors such as lower body mass index, genetic predispositions, and environmental influences may contribute to these differences in response. The safety profile of deucravacitinib is favorable, with low rates of serious adverse events and stable laboratory parameters. This review underscores the need for further research to investigate the genetic, metabolic, and environmental factors that may influence treatment outcomes, aiming to optimize personalized treatment strategies for East Asian patients with psoriasis. Full article

Beyond their metabolic effect, sodium–glucose cotransporter-2 (SGLT-2) inhibitors reduce the risk of heart failure and have cardiovascular and nephroprotective effects, yet their exact mechanism of action remains unclear. This prospective study included 40 patients with type 2 diabetes whose physician initiated SGLT-2 inhibitor therapy. Prior to and 4 weeks after the initiation of SGLT-2 inhibitors, in addition to routine clinical and laboratory measurements, hydroxyl free radical and neuropathic evaluations were performed. Body weight, body mass index (BMI), fasting glucose, fructosamine, and albuminuria decreased significantly, whereas red blood cell (RBC) count, hemoglobin, hematocrit, mean corpuscular volume (MCV), and platelet count increased significantly. Urinary o-tyrosine/p-tyrosine and (m-tyrosine+o-tyrosine)/p-tyrosine ratios were significantly reduced, suggesting diminished hydroxyl free radical production. Patients with neuropathy, identified by abnormal baseline current perception threshold (CPT) values, showed significant improvements. Significant correlations between RBCs, platelet parameters, albuminuria, and hydroxyl free radical markers disappeared after SGLT-2 treatment and changes in hydroxyl free radical markers correlated positively with CPT changes. Our results suggest that short-term SGLT-2 inhibition recalibrates metabolic, hematologic, renal, and neuropathic endpoints simultaneously, presumably through attenuating abnormal ortho- and meta-tyrosine incorporation into signaling proteins. Further studies are required to confirm long-term durability and examine whether additional strategies, such as supplementation of the physiological p-tyrosine, could amplify these benefits. Full article

The src-homology 2 domain-containing phosphatase 2 (SHP2) is a human cytoplasmic protein tyrosine phosphatase that plays a crucial role in cellular signal transduction. Aberrant activation and mutations of SHP2 are associated with tumor growth and immune suppression, thus making it a potential target for cancer therapy. Initially, researchers sought to develop inhibitors targeting SHP2’s catalytic site (protein tyrosine phosphatase domain, PTP). Due to limitations such as conservativeness and poor membrane permeability, SHP2 was once considered a challenging drug target. Nevertheless, with the in-depth investigations into the conformational switch mechanism from SHP2’s inactive to active state and the emergence of various SHP2 allosteric inhibitors, new hope has been brought to this target. In this study, we investigated the interaction models of various allosteric inhibitors with SHP2 using molecular dynamics simulations. Meanwhile, we explored the free energy landscape of SHP2 activation using enhanced sampling technique (meta-dynamics simulations), which provides insights into its conformational changes and activation mechanism. Furthermore, to biophysically interpret high-dimensional simulation trajectories, we employed interpretable machine learning methods, specifically extreme gradient boosting (XGBoost) with Shapley additive explanations (SHAP), to comprehensively analyze the simulation data. This approach allowed us to identify and highlight key structural features driving SHP2 conformational dynamics and regulating the activity of the allosteric inhibitor. These studies not only enhance our understanding of SHP2’s conformational switch mechanism but also offer crucial insights for designing potent allosteric SHP2 inhibitors and addressing drug resistance issues. Full article

(1) Background: Branched-chain and aromatic amino acids (BCAAs/AAAs) have been considered as markers of type 2 diabetes (T2D); however, studies on associations between these metabolites and T2D and cardiometabolic traits in Hispanic populations are limited. The aim of this study was to examine the associations between baseline BCAAs (isoleucine, leucine, valine)/AAAs (phenylalanine, tyrosine) and prevalent and incident T2D, as well as baseline and longitudinal (2 year) changes in cardiometabolic traits (measures of glycemia, dyslipidemia, inflammation, and obesity) in two large cohorts of adults of Puerto Rican descent. (2) Methods: We included participants of the Boston Puerto Rican Health Study (BPRHS, n = 670) and San Juan Overweight Adult Longitudinal study (SOALS, n = 999) with available baseline metabolite and covariate data. T2D diagnosis was defined based on American Diabetes Association criteria. Multivariable logistic (for baseline T2D), Poisson (for incident T2D), and linear (for cardiometabolic traits) regression models were used; cohort-specific results were combined in the meta-analysis and adjusted for multiple comparisons. (3) Results: Higher baseline BCAAs were associated with higher odds of prevalent T2D (OR_{1SD BCAA score} = 1.46, 95% CI: 1.34–1.59, p < 0.0001) and higher risk of incident T2D (IRR_{1SD BCAA score} = 1.24, 95% CI: 1.13–1.37, p < 0.0001). In multivariable longitudinal analysis, higher leucine and valine concentrations were associated with 2-year increase in insulin (beta _{1SD leucine} = 0.37 mcU/mL, 95% CI: 0.11–0.63, p < 0.05; beta _{1SD valine} = 0.43 mcU/mL, 95% CI: 0.17–0.68, p < 0.01). Tyrosine was a significant predictor of incident T2D (IRR = 1.31, 95% CI: 1.09–1.58, p < 0.05), as well as 2 year increases in HOMA-IR (beta _{1SD tyrosine} = 0.13, 95% CI: 0.04–0.22, p < 0.05) and insulin concentrations (beta _{1SD tyrosine} = 0.37 mcU/mL, 95% CI: 0.12–0.61, p < 0.05). (4) Conclusions: Our results confirmed the associations between BCAAs and prevalent and incident T2D, as well as concurrent measures of glycemia, dyslipidemia, and obesity, previously reported in predominantly White and Asian populations. Baseline leucine, valine, and tyrosine were predictors of 2 year increases in insulin, whereas tyrosine was a significant predictor of deteriorating insulin resistance over time. Our study suggests that BCAAs and tyrosine could serve as early markers of future glycemic changes in Puerto Ricans. Full article

We performed a systematic review and meta-analysis to assess the efficacy of EGFR-tyrosine kinase inhibitors (TKI) retreatment in advanced/metastatic non-small-cell lung cancer (NSCLC) patients. We systematically searched PubMed, Embase, Cochrane databases, ASCO, and ESMO websites for studies evaluating EGFR-TKI retreatment in advanced/metastatic NSCLC patients. All analyses were performed using R software (v.4.2.2). We included 19 studies (9 CTs and 10 retrospective cohorts) with a total of 886 patients. In a pooled analysis of all patients during retreatment with TKI, median OS was 11.7 months (95% confidence interval [CI] 10.2–13.4 months) and PFS was 3.2 months (95% CI 2.5–3.9 months). ORR was 15% (95% CI 10–21%) and DCR was 61% (95% CI 53–67%). The subanalysis by generation of TKI in the rechallenge period revealed a slightly better ORR for patients on 3rd generation TKI (p = 0.05). Some limitations include the high heterogeneity of some of the analyses and inability to perform certain subanalyses. Our results unequivocally support the benefit of EGFR-TKI rechallenge in EGFR-mutated NSCLC patients progressing on TKI treatment after a TKI-free interval. These findings may be especially valuable in areas where access to novel therapeutic drugs and clinical trials is limited. Full article

Preeclampsia (PE) is a multifactorial pregnancy disorder characterized by hypertension and proteinuria, posing significant risks to both maternal and fetal health. Despite extensive research, its complex pathophysiology remains incompletely understood. This narrative review aims to elucidate the intricate mechanisms contributing to PE, focusing on abnormal placentation, maternal systemic response, oxidative stress, inflammation, and genetic and epigenetic factors. This review synthesizes findings from recent studies, clinical trials, and meta-analyses, highlighting key molecular and cellular pathways involved in PE. The review integrates data on oxidative stress biomarkers, angiogenic factors, immune interactions, and mitochondrial dysfunction. PE is initiated by poor placentation due to inadequate trophoblast invasion and improper spiral artery remodeling, leading to placental hypoxia. This triggers the release of anti-angiogenic factors such as soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng), causing widespread endothelial dysfunction and systemic inflammation. Oxidative stress, mitochondrial abnormalities, and immune dysregulation further exacerbate the condition. Genetic and epigenetic modifications, including polymorphisms in the Fms-like tyrosine kinase 1 (FLT1) gene and altered microRNA (miRNA) expression, play critical roles. Emerging therapeutic strategies targeting oxidative stress, inflammation, angiogenesis, and specific molecular pathways like the heme oxygenase-1/carbon monoxide (HO-1/CO) and cystathionine gamma-lyase/hydrogen sulfide (CSE/H2S) pathways show promise in mitigating preeclampsia’s effects. PE is a complex disorder with multifactorial origins involving abnormal placentation, endothelial dysfunction, systemic inflammation, and oxidative stress. Despite advances in understanding its pathophysiology, effective prevention and treatment strategies remain limited. Continued research is essential to develop targeted therapies that can improve outcomes for both mothers and their babies. Full article

Bioluminescence and fluorescence resonance energy transfer (BRET and FRET) together with the proximity ligation method revealed the existence of G-protein-coupled receptors, Ionotropic and Receptor tyrosine kinase heterocomplexes, e.g., A2AR–D2R, GABAA–D5R, and FGFR1–5-HT1AR heterocomplexes. Molecular integration takes place through allosteric receptor–receptor interactions in heteroreceptor complexes of synaptic and extra-synaptic regions. It involves the modulation of receptor protomer recognition, signaling and trafficking, as well as the modulation of behavioral responses. Allosteric receptor–receptor interactions in hetero-complexes give rise to concepts like meta-modulation and protein modulation. The introduction of receptor–receptor interactions was the origin of the concept of meta-modulation provided by Katz and Edwards in 1999, which stood for the fine-tuning or modulation of nerve cell transmission. In 2000–2010, Ribeiro and Sebastiao, based on a series of papers, provided strong support for their view that adenosine can meta-modulate (fine-tune) synaptic transmission through adenosine receptors. However, another term should also be considered: protein modulation, which is the key feature of allosteric receptor–receptor interactions leading to learning and consolidation by novel adapter proteins to memory. Finally, it must be underlined that allosteric receptor–receptor interactions and their involvement both in brain disease and its treatment are of high interest. Their pathophysiological relevance has been obtained, especially for major depressive disorder, cocaine use disorder, and Parkinson’s disease. Full article

Introduction: The epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in combination with anti-vascular endothelial growth factor receptor (VEGFR) agents have shown improved survival outcomes in recent studies. However, its efficacy related to survival outcomes as a first- or second-line agent and based on generations remains to be explored. This study estimated the survival outcomes of EGFR-TKIs plus anti-VEGFR in combination in defined populations of advanced non-small cell lung cancer (NSCLC) patients overall, as a first- or second line of treatment, with different generations of EGFR-TKIs and EGFR-TKIs plus bevacizumab combination as a subgroup. Methods: A literature search was conducted using PubMed, SCOPUS, Cochrane Library, and ClinicalTrials.gov databases through June 2023 to identify primary research reporting the survival outcomes of EGFR-TKIs in combination with anti-VEGFR agents in patients with advanced NSCLC. Studies that were single-arm, published in non-English languages, and had missing data on survival outcomes were excluded. A meta-analysis was conducted to generate pooled hazard ratios (HRs) with 95% confidence intervals (CI) for overall survival (OS) and progression-free survival (PFS). Methodological quality and risk of bias in studies were assessed using the Cochrane Handbook for Systematic Reviews of Interventions risk of bias tool. Results: A total of 20 randomized controlled trials were included in the qualitative synthesis, and 11 (2182 participants) were included in the meta-analysis. Patients’ median age ranged from 58 to 68 years; 36% to 70% of patients were female; most of them had IIIa/b to IV stage cancer. In meta-analyses, the EGFR-TKIs plus anti-VEGFR combination resulted in improved PFS (HR, 0.73; 95% CI: 0.61, 0.86; p < 0.00001) in patients with advanced NSCLC but had no impact on OS (HR, 0.93; 95% CI: 0.79, 1.10; p = 0.41). The first line of treatment and first-generation EGFR-TKIs with the combination also improved the PFS (HR, 0.64; 95% CI: 0.57, 0.71; p < 0.00001; HR, 0.63; 95% CI: 0.56, 0.71; p < 0.00001) respectively, however, had no impact on OS. Conclusions: Our meta-analysis indicated EGFR-TKIs with anti-VEGFR in combination not only improved overall PFS but also showed similar results to a first line and first-generation agent compared to EGFR-TKI alone. Full article