Understanding the Transepithelial Transport and Transbilayer Diffusion of the Antihypertensive Peptide Asn-Cys-Trp: Insights from Caco-2 Cell Monolayers and the DPPC Model Membrane.

Understanding the transport mechanism of the peptide Asn-Cys-Trp (NCW) is crucial to improving its intestinal absorption and bioavailability. This study investigated the absorption of NCW through Caco-2 cell monolayers and its interaction with the DPPC bilayers. Results revealed that after a 3 h incubation, the Papp (AP-BL) and Papp (BL-AP) values of NCW at a concentration of 5 mmol/L were (22.24 ± 4.52) × 10-7 and (6.63 ± 2.31) × 10-7 cm/s, respectively, with the transport rates of 1.59 ± 0.32 and 0.62 ± 0.20%, indicating its moderate absorption. NCW was found to be transported via PepT1 and paracellular transport pathways, as evidenced by the significant impact of Gly-Pro and cytochalasin D on the Papp values. Moreover, NCW upregulated ZO-1 mRNA expression. Further investigation of the ZO-1-mediated interaction between NCW and tight junction proteins will contribute to a better understanding of the paracellular transport mechanism of NCW. The interaction between NCW and the DPPC bilayers was predominantly driven by entropy. NCW permeated the bilayers through electrostatic, hydrogen bonding, and hydrophobic interactions, resulting in increased fluidity, flexibility, and disorder as well as phase transition and phase separation of the bilayers.

Adjunctive pascolizumab in rifampicin-susceptible pulmonary tuberculosis: proof-of-concept, partially-randomised, double-blind, placebo-controlled, dose-escalation trial.

BACKGROUND: Interleukin-4 (IL-4), increased in tuberculosis infection, may impair bacterial killing. Blocking IL-4 confers benefit in animal models. We evaluated safety and efficacy of pascolizumab (humanised anti-IL-4 monoclonal antibody) as adjunctive tuberculosis treatment. METHODS: Participants with rifampicin-susceptible pulmonary tuberculosis received a single intravenous infusion of pascolizumab or placebo; and standard 6-month tuberculosis treatment. Pascolizumab dose increased in successive cohorts: [1] non-randomised 0.05 mg/kg (n = 4); [2] non-randomised 0.5 mg/kg (n = 4); [3] randomised 2.5 mg/kg (n = 9) or placebo (n = 3); [4] randomised 10 mg/kg (n = 9) or placebo (n = 3). Co-primary safety outcome was study-drug-related grade 4 or serious adverse event (G4/SAE); in all cohorts (1-4). Co-primary efficacy outcome was week-8 sputum culture time-to-positivity (TTP); in randomised cohorts (3-4) combined. RESULTS: Pascolizumab levels exceeded IL-4 50% neutralising dose for 8 weeks in 78-100% of participants in cohorts 3-4. There were no study-drug-related G4/SAEs. Median week-8 TTP was 42 days in pascolizumab and placebo groups (p = 0.185). Rate of TTP increase was greater with pascolizumab (difference from placebo 0.011 [95% Bayesian credible interval 0.006 to 0.015] log10TTP/day. CONCLUSIONS: There was no evidence to suggest blocking IL-4 was unsafe. Preliminary efficacy findings are consistent with animal models. This supports further investigation of adjunctive anti-IL-4 interventions for tuberculosis in larger phase 2 trials.

Does dose reduction of afatinib affect treatment outcomes of patients with EGFR-mutant metastatic non-small cell lung cancer in real-world clinical practice?

Background: Afatinib can be started at a dose lower than the recommended starting dose of 40 mg/day for the treatment of epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC), however treatment outcomes in real-world clinical practice remains unclear. Methods: This retrospective study of patients with NSCLC from 18 major hospitals (public, private or university teaching hospitals) enrolled in Malaysia's National Cardiovascular and Thoracic Surgical Database (NCTSD) assessed the efficacy of lower doses of afatinib on treatment outcomes in a real-world clinical practice. Data on clinical characteristics, afatinib dosing, and treatment outcomes for patients included in NCTSD from 1st January 2015 to 31st December 2020 were analyzed. Results: Of the 133 patients studied, 94.7% had adenocarcinoma. Majority of the patients (60.9%) had EGFR exon 19 deletion and 23.3% had EGFR exon 21 L858R point mutation. The mean age of patients was 64.1 years and majority (83.5%) had Eastern Cooperative Oncology Group performance status of 2-4 at diagnosis. The most common afatinib starting doses were 40 mg (37.6%), 30 mg (29.3%), and 20 mg (26.3%) once daily (OD), respectively. A quarter of patients had dose reduction (23.3%) due to side effects or cost constraints. Majority of the patients had partial response to afatinib (63.2%) whilst 2.3% had complete response. Interestingly, the objective response rate was significantly higher (72.3%) with afatinib OD doses of less than 40 mg compared to 40 mg (54.0%) (P=0.032). Patients on lower doses of afatinib were two times more likely to achieve an objective response [odds ratio =2.64; 95% confidence interval (CI): 1.20-5.83; P=0.016]. These patients had a numerically but not statistically longer median time to treatment failure (TTF). Median TTF (95% CI) for the overall cohort was 12.4 (10.02-14.78) months. Median overall survival (95% CI) was 21.30 (15.86-26.75) months. Conclusions: Lower afatinib doses (<40 mg OD) could be equally effective as standard dose in patients with EGFR-mutant advanced NSCLC and may be more suited to Asian patients, minimizing side effects that may occur at higher dosages of afatinib leading to dose interruptions and affecting treatment outcomes.

[In vitro expression and functional analyses of the mutants p.R243Q, p.R241C and p.Y356X of the human phenylalanine hydroxylase]. / äººè‹¯ä¸™æ°¨é ¸ç¾ŸåŒ–é ¶çªå˜ä½“p.R243Q、p.R241C和p.Y356Xçš„ä½“å¤–è¡¨è¾¾åŠåŠŸèƒ½ç ”ç©¶.

OBJECTIVES: To study the in vitro expression of three phenylalanine hydroxylase (PAH) mutants (p.R243Q, p.R241C, and p.Y356X) and determine their pathogenicity. METHODS: Bioinformatics techniques were used to predict the impact of PAH mutants on the structure and function of PAH protein. Corresponding mutant plasmids of PAH were constructed and expressed in HEK293T cells. Quantitative reverse transcription polymerase chain reaction was used to measure the mRNA expression levels of the three PAH mutants, and their protein levels were assessed using Western blot and enzyme-linked immunosorbent assay. RESULTS: Bioinformatics analysis predicted that all three mutants were pathogenic. The mRNA expression levels of the p.R243Q and p.R241C mutants in HEK293T cells were similar to the mRNA expression level of the wild-type control (P>0.05), while the mRNA expression level of the p.Y356X mutant significantly decreased (P<0.05). The PAH protein expression levels of all three mutants were significantly reduced compared to the wild-type control (P<0.05). The extracellular concentration of PAH protein was reduced in the p.R241C and p.Y356X mutants compared to the wild-type control (P<0.05), while there was no significant difference between the p.R243Q mutant and the wild type control (P>0.05). CONCLUSIONS: p.R243Q, p.R241C and p.Y356X mutants lead to reduced expression levels of PAH protein in eukaryotic cells, with p.R241C and p.Y356X mutants also affecting the function of PAH protein. These three PAH mutants are to be pathogenic.

Determining hyperelastic properties of the constituents of the mussel byssus system.

The mussel byssus system, comprising the adhesive plaque, distal thread, and proximal thread, plays a crucial role in the survival of marine mussels amongst ocean waves. Whilst recent research has explored the stress-strain behaviour of the distal thread and proximal thread through experimental approaches, little attention has been paid to the potential analytical or modelling methods within the current literature. In this work, analytical and finite element (FE) inverse methods were employed for the first time to identify the hyperelastic mechanical properties of both the plaque portion and the proximal thread. The results have demonstrated the feasibility of applied inverse methods in determining the mechanical properties of the constituents of the mussel byssus system, with the residual sum of squares of 0.0004 (N2) and 0.01 (mm2) for the proximal thread and the plaque portion, respectively. By leveraging mechanical and optical tests, this inverse methodology offers a simple and powerful means to anticipate the material properties for different portions of the mussel byssus system, thus providing insights into mimetic applications in engineering and material design.

Identifying Regenerated Saplings by Stratifying Forest Overstory Using Airborne LiDAR Data.

Identifying the spatiotemporal distributions and phenotypic characteristics of understory saplings is beneficial in exploring the internal mechanisms of plant regeneration and providing technical assistances for continues cover forest management. However, it is challenging to detect the understory saplings using 2-dimensional (2D) spectral information produced by conventional optical remotely sensed data. This study proposed an automatic method to detect the regenerated understory saplings based on the 3D structural information from aerial laser scanning (ALS) data. By delineating individual tree crown using the improved spectral clustering algorithm, we successfully removed the overstory canopy and associated trunk points. Then, individual understory saplings were segmented using an adaptive-mean-shift-based clustering algorithm. This method was tested in an experimental forest farm of North China. Our results showed that the detection rates of understory saplings ranged from 94.41% to 152.78%, and the matching rates increased from 62.59% to 95.65% as canopy closure went down. The ALS-based sapling heights well captured the variations of field measurements [R2 = 0.71, N = 3,241, root mean square error (RMSE) = 0.26 m, P < 0.01] and terrestrial laser scanning (TLS)-based measurements (R2 = 0.78, N =443, RMSE = 0.23 m, P < 0.01). The ALS-based sapling crown width was comparable with TLS-based measurements (R2 = 0.64, N = 443, RMSE = 0.24 m). This study provides a solution for the quantification of understory saplings, which can be used to improve forest ecosystem resilence through regulating the dynamics of forest gaps to better utilize light resources.

Derivation and application of a parameter for denitrification rates in the Taihu Lake model based on an isotope-labeled denitrification experiment.

In recent years, the total nitrogen concentration in Taihu Lake has decreased significantly. Denitrification, as the main nitrogen removal process, is the key reason for the decrease. Here, the denitrification parameter values in the Environmental Fluid Dynamic Code (EFDC) model were calculated based on isotope-labeled denitrification experiment instead of selecting the recommended values directly. This study further focused on EFDC denitrification parameter derivation with an experimental denitrification rate (Dtot) to reduce simulation errors. According to the EFDC nitrate deposition flux mechanism, the conversion equation between the denitrification rate of the first sediment layer ([Formula: see text]) in EFDC and Dtot was successfully derived. The results revealed a linear correlation between [Formula: see text] and (Dtot)1/2. The [Formula: see text] values of sampling points ranged from 0.25 to 0.27 m·day-1, within the range of model parameters. After substituting [Formula: see text] into the Taihu Lake EFDC model, the average percentage bias and determination coefficient of total nitrogen were 16.25% and 0.87, respectively. The average total nitrogen concentration reduction caused by denitrification at water quality calibration points ranged from 0.027 to 0.305 mg·L-1.

The effects of wind-wave disturbances on sediment resuspension and phosphate release in Lake Chao.

As a typical shallow lake with a wind-generated flow, the resuspension state of sediment and phosphorus release under wind field disturbance plays an important role in controlling lake eutrophication in Lake Chao. In this study, we proposed a combination of experimental analysis of dynamic disturbances, wind-wave disturbance shear stress calculation, and model simulation (experimental-calculative-modeling) to quantitatively investigate the effects of wind-wave disturbances on the resuspension state of Lake Chao bottom sediment and phosphorus release and distribution. The results showed that the release rate of phosphorus from the Lake Chao bottom sediment was affected by the wind field and bottom sediment content, which varied significantly spatially and showed some difference between different seasons. Under the condition of sufficient water body disturbance, the substrate in the Western Lake area of Lake Chao mainly adsorbed phosphate from the water body, while the substrate in the Central Lake area and the Eastern Lake area adsorbed phosphate along with the release. The magnitude of the phosphorus release rate due to sediment resuspension was mainly affected by wind speed, and the distribution of phosphorus content was influenced by the circulation generated by different dominant wind directions. The wind-wave disturbances have a significant effect on the spatial and temporal distribution of phosphorus in Lake Chao, and the proposed experimental-calculative-modeling ensemble can provide relevant technical support for the study of water pollution control strategies and comprehensive remediation and management of Lake Chao.

Salidroside Ameliorates Furan-Induced Testicular Inflammation in Relation to the Gut-Testis Axis and Intestinal Apoptosis.

Furan is a heat-induced food contaminant, and it causes damage to visceral organs, including the testis. To determine the mechanism of the damage to the testis, a mouse model treated with furan (8 mg/kg bw/day) and salidroside (SAL, 10/20/40 mg/kg bw/day) was established, and levels of testicular functional markers and changes of morphology were investigated in furan-induced mice treated with SAL. The change in related proteins and genes suggested that SAL restored the furan-mediated leaky tight junction and triggered the TLR4/MyD88/NF-κB pathway and NLRP3 inflammasome together with inflammation. To find out the gut-testis axis, microbiota PICRUSt analysis and correlation analysis were conducted to investigate the core microbiota and metabolites. The endoplasmic reticulum stress (ERS)-related key protein levels and the result of transmission electron microscopy suggested that SAL inhibited the furan-induced intestinal ERS. The result of TUNEL and levels of apoptosis-related proteins suggested that furan-induced intestinal apoptosis was alleviated by SAL. Collectively, SAL inhibited furan-induced ERS-mediated intestinal apoptosis through modulation of intestinal flora and metabolites, thus strengthening the gut barrier. It inhibited LPS from entering the circulatory system and suppressed the testicular TLR4/MyD88/NF-κB pathway and NLRP3 inflammasome, which alleviated testicular inflammation.

30-Day Readmission Rate of Patients with COPD and Its Associated Factors: A Retrospective Cohort Study from a Tertiary Care Hospital.

Purpose: Readmission of chronic obstructive pulmonary disease (COPD) has been used as a measure of performance for COPD care. This study aimed to determine the rate of readmission of COPD in tertiary care hospital in Malaysia and its associated factors. Patients and Methods: A retrospective cohort study was conducted at a tertiary care hospital in Malaysia from 1st January to 21st May 2019. Seventy admissions for COPD exacerbation involving 58 patients were analyzed. Results: The majority of the patients were male (89.8%), had a mean age of 71.95 ± 7.24 years and a median smoking history of 40 (IQR = 25) pack-years, 84.5% were in GOLD group D and 91.4% had a mMRC grading of 2 or greater. Approximately 60.3% had upper or lower respiratory tract infection as the cause of exacerbation; one in five patients had uncompensated hypercapnic respiratory failure at presentation, and 27.6% needed mechanical ventilatory support. Approximately 43.1% of patients had a history of exacerbation that required hospitalisation in the past year. The mean blood eosinophil concentration was 0.38 ± 0.46 x109 cells/L. The 30-day readmission rate was 20.3%, revisit rate to the emergency room within 30 days after discharge was 3.4%, and in-hospital mortality rate was 1.7%. Among all characteristics, a higher baseline mMRC grade (p = 0.038) and history of exacerbation in the past 1 year (p < 0.001) were statistically associated with 30-day readmission. Conclusion: The 30-day readmission rate for COPD exacerbation in a Malaysian tertiary hospital is similar to the rates in high-income countries. Exacerbation in the previous year and a higher baseline mMRC grading were significant risk factors for 30-day readmission in patients with COPD. Strategies of COPD management should concentrate on improvement of symptoms control by optimisation of pharmacotherapy, and early initiation of pulmonary rehabilitation, and structured integrated care programs to reduce readmission rates.

Central Nervous System Outcomes of Lazertinib Versus Gefitinib in EGFR-Mutated Advanced NSCLC: A LASER301 Subset Analysis.

INTRODUCTION: Lazertinib, a third-generation mutant-selective EGFR tyrosine kinase inhibitor, improved progression-free survival compared with gefitinib in the phase 3 LASER301 study (ClinicalTrials.gov Identifier: NCT04248829). Here, we report the efficacy of lazertinib and gefitinib in patients with baseline central nervous system (CNS) metastases. METHODS: Treatment-naive patients with EGFR-mutated advanced NSCLC were randomized one-to-one to lazertinib (240 mg/d) or gefitinib (250 mg/d). Patients with asymptomatic or stable CNS metastases were included if any planned radiation, surgery, or steroids were completed more than 2 weeks before randomization. For patients with CNS metastases confirmed at screening or subsequently suspected, CNS imaging was performed every 6 weeks for 18 months, then every 12 weeks. End points assessed by blinded independent central review and Response Evaluation Criteria in Solid Tumors version 1.1 included intracranial progression-free survival, intracranial objective response rate, and intracranial duration of response. RESULTS: Of the 393 patients enrolled in LASER301, 86 (lazertinib, n = 45; gefitinib, n = 41) had measurable and or non-measurable baseline CNS metastases. The median intracranial progression-free survival in the lazertinib group was 28.2 months (95% confidence interval [CI]: 14.8-28.2) versus 8.4 months (95% CI: 6.7-not reached [NR]) in the gefitinib group (hazard ratio = 0.42, 95% CI: 0.20-0.89, p = 0.02). Among patients with measurable CNS lesions, the intracranial objective response rate was numerically higher with lazertinib (94%; n = 17) versus gefitinib (73%; n = 11, p = 0.124). The median intracranial duration of response with lazertinib was NR (8.3-NR) versus 6.3 months (2.8-NR) with gefitinib. Tolerability was similar to the overall LASER301 population. CONCLUSIONS: In patients with CNS metastases, lazertinib significantly improved intracranial progression-free survival compared with gefitinib, with more durable responses.

Developing a home-based pulmonary rehabilitation programme for patients with chronic respiratory diseases in Malaysia: A mixed-method feasibility study.

Background: The COVID-19 pandemic has underscored the importance of remote healthcare and home-based interventions, including pulmonary rehabilitation, for patients with chronic respiratory diseases (CRDs). It has also heightened the vulnerability of individuals with underlying respiratory conditions to severe illness from COVID-19, necessitating exploration and assessment of the feasibility of delivering home - pulmonary rehabilitation (home-PR) programmes for CRD management in Malaysia and other countries. Home-based programmes offer a safer alternative to in-person rehabilitation during outbreaks like COVID-19 and can serve as a valuable resource for patients who may be hesitant to visit healthcare facilities during such times. We aimed to assess the feasibility of delivering a home-PR programme for patients with CRDs in Malaysia. Methods: We recruited patients with CRDs from two hospitals in Klang Valley, Malaysia to a home-PR programme. Following centre-based assessment, patients performed the exercises at home (five sessions/week for eight weeks (total 40 sessions)). We monitored the patients via weekly telephone calls and asked about adherence to the programme. We measured functional exercise capacity (6-Minutes Walking Test (6MWT) and Health-Related Quality-of-Life (HRQoL) (COPD Assessment Test (CAT)) at baseline and post-PR at nine weeks. We conducted semi-structured interviews with 12 purposively sampled participants to explore views and feedback on the home-PR programme. The interviews were audio recorded, transcribed verbatim, and analysed thematically. Results: We included 30 participants; two withdrew due to hospitalisation. Although 28 (93%) adhered to the full programme, only 11 (37%) attended the post-PR assessment because COVID-19 movement restrictions in Malaysia at that time prevented attendance at the centre. Four themes emerged from the qualitative analysis: involvement of family and caregivers, barriers to home-PR programme, interactions with peers and health care professionals, and programme enhancement. Conclusion: Despite the COVID-19 pandemic, the home-PR programme proved feasible for remote delivery, although centre-based post-PR assessments were not possible. Family involvement played an important role in the home-PR programme. The delivery of this programme can be further improved to maximise the benefit for patients.

Allicin Alleviates Mitochondrial Dysfunction in Acrylamide-Induced Rat Kidney Involving the Regulation of SIRT1.

Acrylamide (AA), commonly formed in carbohydrate-rich thermally processed foods, exerts harmful effects on the kidney. Allicin, from crushed garlic cloves, exhibits strong biological activities. In the current study, the protection mechanisms of allicin against AA-caused nephrotoxicity were comprehensively examined using an in vivo rat model based on previous research that allicin plays a key role in improving renal function. The results showed that allicin attenuated histological changes of the kidney and ameliorated renal function. Damaged mitochondrial structures, upregulated voltage-dependent anion channel 1 expression, and decreased membrane potential and adenosine 5'-triphosphate levels were observed after AA treatment. Surprisingly, allicin notably reversed the adverse effects. Further, allicin effectively restored mitochondrial function via modulating mitochondrial biogenesis and dynamics, which might be associated with the upregulated expression of sirtuin 1 (SIRT1). Meanwhile, allicin dramatically activated the SIRT1 activity and subsequently inhibited p53 acetylation, prevented the translocation of cytochrome c to the cytoplasm, and reduced the caspase expression, thus further inhibiting mitochondrial apoptosis caused by AA. In summary, the relieving effect of allicin on AA-caused nephrotoxicity lies in its inhibition of mitochondrial dysfunction and mitochondrial apoptosis.

Effects of ultrasound-guided stellate ganglion block on postoperative sore throat and postoperative sleep disturbance after lumbar spine surgery: a randomized controlled trial.

BACKGROUND: Postoperative sore throat and sleep disturbance are prevalent among patients undergoing spinal surgery, and these conditions can substantially impact their postoperative satisfaction and quality of life. The present study aimed to examine the impact of ultrasound-guided stellate ganglion block (SGB) on the occurrence of postoperative sore throat (POST) and postoperative sleep disturbance (PSD) in patients who undergo lumbar spine surgery under general anesthesia. METHODS: Sixty patients were randomly assigned to either the experimental group (SGB group) or the control group (CG). Both groups received the same induction and maintenance drugs. However, the SGB group received a right SGB under ultrasound guidance 15 min before anesthesia induction, while the CG did not receive any block anesthesia intervention before anesthesia induction. We monitored the incidence and severity of POST at 1, 6, 24, and 48 h after surgery in both groups. Additionally, we evaluated the deep sleep quality score on the first, second, and fifth days after surgery in both groups. RESULTS: The incidence of POST at 1 h and 6 h after surgery was significantly lower in the SGB group (10.0% and 13.3%) than in the CG (43.3% and 36.7%) (P < 0.05). The postoperative sore throat scores of the SGB group (0.10 ± 0.31 and 0.17 ± 0.46) at 1 h and 6 h after surgery were lower than those of the CG (0.57 ± 0.73 and 0.50 ± 0.77) (P < 0.05). Moreover, the deep sleep quality score on the first, second, and fifth days after surgery were significantly higher in the CG (5.40 ± 3.37, 4.70 ± 3.19, 4.53 ± 3.44) than in the SGB group (3.87 ± 2.30, 3.13 ± 1.77, 3.03 ± 1.84) (P < 0.05). CONCLUSION: Ultrasound-guided SGB can reduce the incidence and severity of POST and improve PSD in patients undergoing lumbar spine surgery. TRIAL REGISTRATION: This study was registered on Chinese Clinical Trial Registry, (ChiCTR2200065279) on 01/11/2022.

Effects of intraoperative Magnesium sulfate infusion on emergency agitation during general anesthesia in patients undergoing radical mastectomy: a randomized controlled study.

BACKGROUND: Emergency agitation is a common postoperative complication in patients under general anesthesia, which can lead to unpredictable damages such as shedding of drainage tube and bleeding from the wound. The purpose of the study is to investigate whether intraoperative infusion of Magnesium Sulfate reduces the incidence of emergency agitation (EA) in patients undergoing radical mastectomy, and to evaluate its safety and efficacy. METHODS: A total of 70 patients were randomly assigned to two groups: the Magnesium group (M group) and the control group (C group). After a routine intravenous anesthetic induction, patients in the M group received a 30 mg/kg bolus of intravenous magnesium during the first hour and then a continuous infusion of 10 mg/kg ×h until the end of the surgery, patients in the C group received 0.9% saline at the same volume and rate. The sedation-agitation scale (SAS) and the visual analogue scale were used to assess agitation and pain, respectively. RESULTS: Compared to the C group, the M group reduced the incidence of EA significantly (odds ratio 0.26, 95% confidence interval 0.09-0.71, P = 0.009). The postoperative pain score of the magnesium sulfate group(0(0,1)) was lower than that of the control group(2(0,3)) at T0 (P = 0.011). Additionally, the M group required a lower dosage of remifentanil during surgery compared to the C group(300.4 ± 84 versus 559.3 ± 184 µg, respectively, P<0.001). CONCLUSIONS: the intraoperative infusion of magnesium sulfate is a safe and effective method for reducing the incidence of emergency agitation in patients undergoing radical mastectomy. TRAIL REGISTRATION: The study was registered in Chictr.org with the identifier: ChiCTR2300070595 on 18/04/2023.

Lazertinib Versus Gefitinib Tyrosine Kinase Inhibitors in Treatment-Naíve Patients With EGFR-Mutated Advanced NSCLC: Analysis of the Asian Subpopulation in LASER301.

INTRODUCTION: Lazertinib is a third-generation central nervous system-penetrant tyrosine kinase inhibitor targeting mutant EGFR in NSCLC. Lazertinib exhibited improved efficacy versus gefitinib in the LASER301 study; this subset analysis compared lazertinib with gefitinib among Asian patients. METHODS: The phase 3 LASER301 study evaluated lazertinib efficacy and safety in treatment-naive patients with EGFR-mutated (exon 19 deletion or L858R) locally advanced or metastatic NSCLC. Patients were randomized one-to-one and received either lazertinib or gefitinib. The primary end point was investigator-assessed progression-free survival using Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end points included overall survival, objective response rate, duration of response, and safety. RESULTS: Between February 13, 2020, and July 29, 2022, among 258 patients of Asian descent, the median progression-free survival was significantly longer with lazertinib than gefitinib (20.6 versus 9.7 mo; hazard ratio: 0.46; 95% confidence interval [CI]: 0.34-0.63, p < 0.001), and the benefit was consistent across predefined subgroups (exon 19 deletion, L858R, baseline central nervous system metastases). Objective response rate and disease control rates were similar between treatment groups. The median duration of response was 19.4 months (95% CI: 16.6-24.9) versus 9.6 months (95% CI: 6.9-12.4) in the lazertinib versus gefitinib group. Adverse event rates in Asian patients were comparable with the overall LASER301 population. Adverse events leading to discontinuation in the lazertinib and gefitinib groups were 13% and 12%, respectively. CONCLUSIONS: In LASER301, efficacy and safety results in Asian patients were consistent with the overall population. Lazertinib exhibited better efficacy than gefitinib in Asian patients with a tolerable safety profile.

Common driver mutations and programmed death-ligand 1 expression in advanced non-small cell lung cancer in smokers and never smokers.

BACKGROUND: In non-small cell lung cancer (NSCLC), there may be a relationship between programmed death-ligand 1 (PD-L1) expression, driver mutations and cigarette smoking. METHODS: In this single-center retrospective study, the relationship between common driver mutations (EGFR mutation and ALK rearrangement) and PD-L1 expression in advanced NSCLC according to the patients' smoking history was examined. Light, moderate and heavy smokers had smoked < 20, 20-39, and ≥ 40 pack-years, respectively. The level of PD-L1 expression, assessed using Ventana SP263 monoclonal antibody assay, was defined by the tumor proportion score (TPS) as high expression (TPS ≥ 50%), low expression (TPS 1%-49%) and no expression (TPS < 1%). RESULTS: 101 (52.9%) of 191 advanced NSCLC patients were never smokers. EGFR mutations were more common in never smokers (64.4%) than in smokers (17.8%) with advanced NSCLC (P < 0.0001). A higher proportion of smokers (26.7%) had high PD-L1 expression compared to never smokers (13.9%) (P = 0.042). There was a trend for a higher proportion of male NSCLC patients [28 of 115 (24.3%)] than female patients [10 of 76 (13.2%)] to have high PD-L1 expression (P = 0.087]. High PD-L1 expression was seen in 32 of 110 (29.1%) patients with EGFR wild-type NSCLC but only in 6 of 81 (7.4%) patients with EGFR-mutant tumors (P < 0.0001). Among the 90 smokers with NSCLC, a higher proportion of heavy smokers (35.8%) than non-heavy smokers (13.5%) had high PD-L1 expression (P = 0.034). In patients with adenocarcinoma, high PD-L1 expression was seen in 25 of 77 (32.5%) patients with EGFR wild-type tumors but only in 4 of 70 (5.7%) patients with EGFR-mutant tumors (P < 0.0001). Among patients with adenocarcinoma, a significantly higher proportion of ever smokers (29.3%) than never smokers (13.5%) had high PD-L1 expression (P = 0.032). Among smokers with adenocarcinoma, a significantly higher proportion of heavy smokers (44.1%) than non-heavy smokers (8.3%) had high PD-L1 expression (P = 0.004). On multivariate analysis, after adjusting for gender and smoking status, heavy smoking and EGFR wild-type tumors remained significantly associated with high PD-L1 expression in NSCLCs and also in adenocarcinoma. CONCLUSIONS: Heavy smoking and EGFR wild-type tumors were significantly associated with high PD-L1 expression in NSCLCs and also in adenocarcinoma.

Lazertinib Versus Gefitinib as First-Line Treatment in Patients With EGFR-Mutated Advanced Non-Small-Cell Lung Cancer: Results From LASER301.

PURPOSE: Lazertinib is a potent, CNS-penetrant, third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor. This global, phase III study (LASER301) compared lazertinib versus gefitinib in treatment-naïve patients with EGFR-mutated (exon 19 deletion [ex19del]/L858R) locally advanced or metastatic non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients were 18 years and older with no previous systemic anticancer therapy. Neurologically stable patients with CNS metastases were allowed. Patients were randomly assigned 1:1 to lazertinib 240 mg once daily orally or gefitinib 250 mg once daily orally, stratified by mutation status and race. The primary end point was investigator-assessed progression-free survival (PFS) by RECIST v1.1. RESULTS: Overall, 393 patients received double-blind study treatment across 96 sites in 13 countries. Median PFS was significantly longer with lazertinib than with gefitinib (20.6 v 9.7 months; hazard ratio [HR], 0.45; 95% CI, 0.34 to 0.58; P < .001). The PFS benefit of lazertinib over gefitinib was consistent across all predefined subgroups. The objective response rate was 76% in both groups (odds ratio, 0.99; 95% CI, 0.62 to 1.59). Median duration of response was 19.4 months (95% CI, 16.6 to 24.9) with lazertinib versus 8.3 months (95% CI, 6.9 to 10.9) with gefitinib. Overall survival data were immature at the interim analysis (29% maturity). The 18-month survival rate was 80% with lazertinib and 72% with gefitinib (HR, 0.74; 95% CI, 0.51 to 1.08; P = .116). Observed safety of both treatments was consistent with their previously reported safety profiles. CONCLUSION: Lazertinib demonstrated significant efficacy improvement compared with gefitinib in the first-line treatment of EGFR-mutated advanced NSCLC, with a manageable safety profile.

Pathological complete response in an advance stage IIIB non-small cell lung cancer secondary to neoadjuvant osimertinib targeted therapy: A case report and review of literature.

Neoadjuvant chemotherapy is a therapeutic option for potentially resectable non-small cell lung cancer (NSCLC). The role of neoadjuvant targeted therapy (NTT) remains less explored. This case highlights the use of neoadjuvant osimertinib in a case of advanced NSCLC. A 67-year-old woman had a left lower lobe lung mass measuring 5.0 × 5.1 × 7.0 cm with an enlarged subcarinal lymph node (LN) on her positron emission tomography scan. Following biopsy, a diagnosis of stage IIIB N2 (cT3N2M0) EGFR exon 19 deletion mutation-positive lung adenocarcinoma was established. NTT using osimertinib 80 mg once daily was commenced. Subsequent re-imaging at 3 months (ycT2bN2M0), 6 months (ycT1cN2M0) and 9 months showed tumour downstaging and resolution of the subcarinal LN (ycT1cN0M0). She underwent left lower lobectomy with systematic nodal dissection. All surgical specimens demonstrated no evidence of malignant cells (ypT0N0). Osimertinib could be the preferred NTT for potentially resectable NSCLC.