Long-Term Survival Outcomes With First-Line Nivolumab Plus Ipilimumab-Based Treatment in Patients With Metastatic Non-Small Cell Lung Cancer and Tumor PD-L1 <1%: a Pooled Analysis.

INTRODUCTION: Nivolumab plus ipilimumab-based treatment regimens have shown long-term, durable efficacy benefit in patients with metastatic non-small cell lung cancer (NSCLC). Here we report clinical outcomes from a pooled analysis of patients with metastatic NSCLC and tumor programmed death ligand 1 (PD-L1) <1% treated with first-line nivolumab plus ipilimumab with or without two cycles of chemotherapy versus up to four cycles of chemotherapy in the randomized phase 3 CheckMate 227 and CheckMate 9LA studies. METHODS: Patients were aged ≥18 years and had stage IV/recurrent NSCLC with no sensitizing EGFR/ALK alterations. Assessments included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), duration of response (DOR), and safety. RESULTS: In patients with tumor PD-L1 <1% in the nivolumab plus ipilimumab with or without chemotherapy (n = 322) versus chemotherapy (n = 315) arms, median OS was 17.4 versus 11.3 months, respectively, (hazard ratio [HR] = 0.64; 95% confidence interval [CI]: 0.54-0.76; 5-year OS rate, 20% versus 7%) at a median follow-up of 73.7 months. OS benefit was observed across key subgroups, including difficult-to-treat populations such as those with baseline brain metastases (HR = 0.44; 95% CI: 0.26-0.75) or squamous NSCLC (HR = 0.51; 95% CI: 0.36-0.72). In the overall pooled population, median PFS was 5.4 versus 4.9 months (HR = 0.72; 95% CI: 0.60-0.87; 5-year PFS rate, 9% versus 2%), ORR was 29% versus 22%, and median DOR was 18.0 versus 4.6 months. No new safety signals were observed. CONCLUSION: Nivolumab plus ipilimumab with or without chemotherapy provides a long-term, durable clinical benefit in patients with metastatic NSCLC and tumor PD-L1 <1%, supporting the use of this strategy as a first-line treatment option in this population with high unmet need.

Individual domain characteristics determined by second-harmonic generation diffractometer for multi-domain multiferroics.

We investigated the multi-domain states of a multiferroic La-doped BiFeO3 (BLFO) thin film by examining diffraction patterns in optical second-harmonic generation (SHG) measurement. By directing a laser onto the domain wall within the domain-patterned sample, we observed clear diffraction signatures of SHG waves generated from two ferroelectric domains. We explained the experimental results of the diffraction patterns, including the intensity distribution and the polarization characteristics, using Fresnel propagation of SHG waves. From this, we could determine the amplitude and phase of the SHG waves generated from each domain, and figure out not only the polarization direction of each ferroelectric domain but also the phase related to the complex-valued second-order susceptibility tensor. Consequently, we could present SHG diffractometry as an effective measurement method to reveal the phase details of electric polarization of the multi-domain states of ferroic materials.

Five-year survival in patients with extensive-stage small cell lung cancer treated with atezolizumab in the Phase III IMpower133 study and the Phase III IMbrella A extension study.

OBJECTIVES: IMbrella A is a Phase III extension study that allowed rollover from Roche/Genentech-sponsored atezolizumab trials, including IMpower133, a Phase I/III trial of first-line atezolizumab or placebo plus carboplatin/etoposide in extensive-stage small cell lung cancer. We report outcomes from an exploratory analysis of IMpower133 with extended time-to-event data for patients who rolled over to IMbrella A. MATERIALS AND METHODS: IMpower133 patients could roll over to IMbrella A to receive atezolizumab 1200 mg intravenously every three weeks if they continued to receive atezolizumab at IMpower133 closure or were in survival follow-up after atezolizumab discontinuation. Overall survival and safety were assessed; only serious adverse events and AEs of special interest were collected in IMbrella A. RESULTS: Eighteen of 26 eligible patients rolled over to IMbrella A. At clinical cutoff (March 16, 2023), median follow-up in the atezolizumab plus carboplatin/etoposide arm (IMpower133 and IMbrella A) was 59.4 months. The three-, four-, and five-year overall survival (95 % CI) estimates were 16 % (11 %-21 %), 13 % (8 %-18 %), and 12 % (7 %-17 %), respectively. In IMbrella A, serious adverse events occurred in three patients (16.7 %), and one adverse event of special interest was reported (grade two hypothyroidism). CONCLUSION: This long-term analysis of patients from IMbrella A previously enrolled in IMpower133 provides the first report of five-year overall survival outcomes in patients with extensive-stage small cell lung cancer treated with first-line cancer immunotherapy and chemotherapy. While limited by small patient numbers and lack of long-term data for the IMpower133 control arm, exploratory overall survival analyses in patients treated with atezolizumab plus carboplatin/etoposide compared favorably with historical data with chemotherapy alone. NCT03148418.

Trehalose catalytic shift is an intrinsic factor in Mycobacterium tuberculosis that enhances phenotypic heterogeneity and multidrug resistance.

Drug-resistance (DR) in many bacterial pathogens often arises from the repetitive formation of drug-tolerant bacilli, known as persisters. However, it is unclear whether Mycobacterium tuberculosis (Mtb), the bacterium that causes tuberculosis (TB), undergoes a similar phenotypic transition. Recent metabolomics studies have identified that a change in trehalose metabolism is necessary for Mtb to develop persisters and plays a crucial role in metabolic networks of DR-TB strains. The present study used Mtb mutants lacking the trehalose catalytic shift and showed that the mutants exhibited a significantly lower frequency of the emergence of DR mutants compared to wildtype, due to reduced persister formation. The trehalose catalytic shift enables Mtb persisters to survive under bactericidal antibiotics by increasing metabolic heterogeneity and drug tolerance, ultimately leading to development of DR. Intriguingly, rifampicin (RIF)-resistant bacilli exhibit cross-resistance to a second antibiotic, due to a high trehalose catalytic shift activity. This phenomenon explains how the development of multidrug resistance (MDR) is facilitated by the acquisition of RIF resistance. In this context, the heightened risk of MDR-TB in the lineage 4 HN878 W-Beijing strain can be attributed to its greater trehalose catalytic shift. Genetic and pharmacological inactivation of the trehalose catalytic shift significantly reduced persister formation, subsequently decreasing the incidence of MDR-TB in HN878 W-Beijing strain. Collectively, the trehalose catalytic shift serves as an intrinsic factor of Mtb responsible for persister formation, cross-resistance to multiple antibiotics, and the emergence of MDR-TB. This study aids in the discovery of new TB therapeutics by targeting the trehalose catalytic shift of Mtb.

Association of TP53 Mutation Status and Sex with Clinical Outcome in NSCLC Treated with Immune Checkpoint Inhibitors: A Retrospective Cohort Study.

Purpose: Some studies suggest that TP53 mutations are associated with the response to immune checkpoint inhibitors (ICI) in patients with non-small cell lung cancer (NSCLC) and also contribute to sex disparities in several cancers. Thus, we hypothesized that TP53 mutations might serve as sex-dependent genomic biomarkers of ICI treatment response in patients with NSCLC. Materials and Methods: Clinical data of 100 patients with metastatic NSCLC treated with ICI monotherapy at Seoul National University Bundang Hospital (SNUBH) were retrospectively reviewed. Genomic and clinical datasets of TCGA and an ICI-treated lung cancer cohort (cBioPortal) were also analyzed. Results: In SNUBH cohort, no statistically significant difference was observed in disease control rate per the TP53 mutation status (p=0.503); however, female patients with TP53 mutated (MT) had a significantly prolonged median progression-free survival (PFS) compared to wild-type (WT) (6.1 months in TP53 MT vs. 2.6 months in TP53 WT; p=0.021). PD-L1 high (≥50%) expression was significantly enriched in female patients with TP53 MT (p=0.001). The analysis from publicly available dataset also revealed that females with NSCLC with TP53 MT showed significantly longer PFS than those with TP53 WT (p<0.001). In TCGA analysis, expression of immune-related genes, and TMB score in TP53 MT females were higher than in males without TP53 MT. Conclusion: Female patients with NSCLC with TP53 mutations had high PD-L1 expression and showed favorable clinical outcomes following ICI therapy, suggesting a need for further research to explore the role of TP53 mutations for sex disparities in response to ICI therapy.

Phase III KEYNOTE-789 Study of Pemetrexed and Platinum With or Without Pembrolizumab for Tyrosine Kinase Inhibitor‒Resistant, EGFR-Mutant, Metastatic Nonsquamous Non-Small Cell Lung Cancer.

PURPOSE: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are standard first-line therapy for EGFR-mutant, metastatic non-small cell lung cancer (NSCLC); however, most patients experience disease progression. We report results from the randomized, double-blind, phase III KEYNOTE-789 study of pemetrexed and platinum-based chemotherapy with or without pembrolizumab for TKI-resistant, EGFR-mutant, metastatic nonsquamous NSCLC (ClinicalTrials.gov identifier: NCT03515837). METHODS: Adults with pathologically confirmed stage IV nonsquamous NSCLC, documented DEL19 or L858R EGFR mutation, and progression after EGFR-TKI treatment were randomly assigned 1:1 to 35 cycles of pembrolizumab 200 mg or placebo once every 3 weeks plus four cycles of pemetrexed and carboplatin or cisplatin once every 3 weeks and then maintenance pemetrexed. Dual primary end points were progression-free survival (PFS) and overall survival (OS). Final PFS testing was completed at the second interim analysis (IA2; data cutoff, December 3, 2021); OS was tested at final analysis (FA; data cutoff, January 17, 2023). Efficacy boundaries were one-sided P = .0117 for PFS and OS. RESULTS: Four hundred ninety-two patients were randomly assigned to pembrolizumab plus chemotherapy (n = 245) or placebo plus chemotherapy (n = 247). At IA2, the median PFS was 5.6 months for pembrolizumab plus chemotherapy versus 5.5 months for placebo plus chemotherapy (hazard ratio [HR], 0.80 [95% CI, 0.65 to 0.97]; P = .0122). At FA, the median OS was 15.9 versus 14.7 months, respectively (HR, 0.84 [95% CI, 0.69 to 1.02]; P = .0362). Grade ≥3 treatment-related adverse events occurred in 43.7% of pembrolizumab plus chemotherapy recipients versus 38.6% of placebo plus chemotherapy recipients. CONCLUSION: Addition of pembrolizumab to chemotherapy in patients with TKI-resistant, EGFR-mutant, metastatic nonsquamous NSCLC did not significantly prolong PFS or OS versus placebo plus chemotherapy in KEYNOTE-789.

Longitudinal Analyses of Circulating Tumor DNA for the Detection of EGFR Mutation-Positive Advanced NSCLC Progression During Treatment: Data From FLAURA and AURA3.

INTRODUCTION: EGFR tyrosine kinase inhibitor (EGFR-TKI)-sensitizing and -resistance mutations may be detected in plasma through circulating tumor DNA (ctDNA). Circulating tumor DNA level changes reflect alterations in tumor burden and could be a dynamic indicator of treatment effect. This analysis aimed to determine whether longitudinal EGFR-mutation ctDNA testing could detect progressive disease (PD) before radiologic detection. METHODS: This was a retrospective, exploratory ctDNA analysis in two phase 3 trials (FLAURA, NCT02296125; AURA3, NCT02151981). Patients had treatment-naïve (FLAURA) or EGFR-TKI pre-treated (AURA3) advanced NSCLC with EGFR mutations and on-study PD (RECIST [Response Evaluation Criteria in Solid Tumors]), with a baseline ctDNA result and EGFR-mutation ctDNA monitoring beyond Cycle 3 Day 1. Patients received osimertinib versus comparator EGFR-TKIs (FLAURA) or chemotherapy (AURA3). Outcomes included time from ctDNA PD to RECIST PD and the first subsequent treatment (FLAURA only). RESULTS: Circulating tumor DNA PD preceded or co-occurred with RECIST-defined PD in 93 out of 146 patients (64%) in FLAURA and 82 out of 146 patients (56%) in AURA3. Median time from ctDNA PD to RECIST-defined PD (mo) was 3.4 and 2.6 in the osimertinib and comparator EGFR-TKI arms (FLAURA) and 2.8 and 1.5 in the osimertinib and chemotherapy arms (AURA3). In FLAURA, the median time from ctDNA PD to the first subsequent treatment (mo) was 6.0 and 4.7 in the osimertinib (n = 51) and comparator EGFR-TKI arms (n = 70). CONCLUSIONS: Among patients with EGFR mutation-positive advanced NSCLC receiving EGFR-TKI or chemotherapy with ctDNA data and RECIST-defined PD, ctDNA PD preceded/co-occurred with RECIST-defined PD in approximately 60% of cases. Longitudinal ctDNA monitoring may detect PD before radiologic PD.

Real-time dynamics of angular momentum transfer from spin to acoustic chiral phonon in oxide heterostructures.

Chiral phonons have recently been explored as a novel degree of freedom in quantum materials. The angular momentum carried by these quasiparticles is generated by the breaking of chiral degeneracy of phonons, owing to the chiral lattice structure or the rotational motion of ions of the material. In ferromagnets, a mechanism for generating non-equilibrium chiral phonons has been suggested, but their temporal evolution, which obeys Bose-Einstein statistics, remains unclear. Here we report the real-time dynamics of thermalized chiral phonons in an artificial superlattice composed of ferromagnetic metallic SrRuO3 and non-magnetic insulating SrTiO3. Following the photo-induced ultrafast demagnetization in the SrRuO3 layer, we observed the appearance of a magneto-optic signal in the superlattice, which is absent in the SrRuO3 single films. This magneto-optic signal exhibits thermally driven dynamic properties and a clear correlation with the thickness of the non-magnetic SrTiO3 layer, implying that it originates from thermalized chiral phonons. We use numerical calculations considering the magneto-elastic coupling in SrRuO3 to validate our experimental observations and the angular momentum transfer mechanism between the lattice and spin systems in ferromagnetic systems and also to the non-magnetic system.

Total Synthesis and Bioactivity Profile of (+)-Ieodomycins A and B and their Stereoisomers.

Herein, we report the first- and second-generation syntheses of (+)-ieodomycins A and B and their stereoisomers via the late-stage elaboration of their conjugated E-diene side chains. Key steps for successful synthesis included Keck asymmetric allylation to introduce a hydroxyl group at the C5 position, consecutive Wipf's carboalumination modification, iodination, Sharpless asymmetric dihydroxylation, one-carbon homologation via cyanation, Mukaiyama lactonization, and Stille cross-coupling to form the conjugated E-diene moiety. Further, the preliminary in vitro bioactivity profile against various disease-related molecular targets and cell lines was investigated. Results indicated that compounds 30b and 30c, diastereoisomers of (+)-ieodomycin B (2), serve as α-glucosidase inhibitors, while compounds 30b and 30d inhibit the angiotensin-converting enzyme.

Epacadostat plus pembrolizumab versus placebo plus pembrolizumab as first-line treatment for metastatic non-small cell lung cancer with high levels of programmed death-ligand 1: a randomized, double-blind phase 2 study.

BACKGROUND: Pembrolizumab is a first-line therapy for certain patients with advanced/metastatic non-small cell lung cancer (NSCLC). Combining pembrolizumab with other immunotherapies may enhance tumor cell killing and clinical outcomes. Epacadostat is a selective inhibitor of indoleamine 2,3-dioxygenase 1, an immuno-regulatory enzyme involved in tryptophan to kynurenine metabolism that inhibits T cell-mediated immune responses. METHODS: In this randomized phase II study, patients with metastatic NSCLC expressing high (≥ 50%) programmed death-ligand 1 (PD-L1) levels received pembrolizumab 200 mg every 21 days plus oral epacadostat 100 mg twice daily (combination) or matching placebo (control). The primary objective was objective response rate (ORR); secondary objectives were progression-free survival (PFS), overall survival (OS), duration of response (DOR) and safety/tolerability. RESULTS: 154 patients were randomized (77 per group). Median (range) follow-up was 6.8 months (0.1-11.4) and 7.0 months (0.2-11.9) in the combination and control groups, respectively Confirmed ORR was similar between groups (combination: 32.5%, 95% CI 22.2-44.1; control: 39.0%, 95% CI 28.0-50.8; difference: - 6.5, 95% CI - 21.5 to 8.7; 1-sided P = 0.8000). Median (range) DOR was 6.2 months (1.9 + to 6.5 +) and not reached (1.9 + to 8.6 +) in the combination and control groups, respectively. Although not formally tested, median PFS was 6.7 and 6.2 months for the combination and control groups, respectively, and median OS was not reached in either group. Circulating kynurenine levels increased from C1D1 to C2D1 (P < 0.01) in the control group and decreased from C1D1 to C2D1 (P < 0.01) in the combination group but were not normalized in most patients. The most frequent serious adverse events (AEs) (≥ 2%) were pneumonia (4.0%), anemia (2.7%), atelectasis (2.7%) and pneumonitis (2.7%) in the combination group and pneumonia (3.9%), pneumonitis (2.6%) and hypotension (2.6%) in the control group. Two deaths due to drug-related AEs were reported, both in the control group. CONCLUSIONS: Addition of epacadostat to pembrolizumab therapy for PD-L1-high metastatic NSCLC was generally well tolerated but did not demonstrate an improved therapeutic effect. Evaluating higher doses of epacadostat that normalize kynurenine levels when given in combination with checkpoint inhibitors may be warranted. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03322540. Registered 10/26/2017.

Neoadjuvant Docetaxel, Oxaliplatin, and S-1 Plus Surgery and Adjuvant S-1 for Resectable Advanced Gastric Cancer: Updated Overall Survival Outcomes From Phase III PRODIGY.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.The phase III PRODIGY study demonstrated that neoadjuvant chemotherapy with docetaxel, oxaliplatin, and S-1 (DOS) followed by surgery and adjuvant S-1 chemotherapy (CSC) improved progression-free survival (PFS) compared with surgery followed by adjuvant S-1 (SC) for patients with resectable locally advanced gastric cancer (LAGC) with clinical T2-3N+ or T4Nany disease. The primary end point was PFS. Overall survival (OS) was the secondary end point. We herein report the long-term follow-up outcomes, including OS, from this trial. A total of 238 and 246 patients were randomly assigned to the CSC and SC arms, respectively, and were treated (full analysis set). As of the data cutoff (September 2022), the median follow-up duration of the surviving patients was 99.5 months. Compared with SC, CSC significantly increased the OS (adjusted hazard ratio [HR], 0.72; stratified log-rank P = .027) with an 8-year OS rate of 63.0% and 55.1% for the CSC and SC arms, respectively. CSC also significantly improved the PFS (HR, 0.70; stratified log-rank P = .016). In conclusion, neoadjuvant DOS chemotherapy, as part of perioperative chemotherapy, prolonged the OS of Asian patients with LAGC relative to patients treated with surgery and adjuvant S-1. It should be considered one of the standard treatment options for patients with LAGC in Asia.

A phase II study of osimertinib in patients with NSCLC harboring EGFR exon 20 insertion: A multicenter trial of the Korean Cancer Study Group (LU17-19).

BACKGROUND: Epidermal growth factor receptor (EGFR) exon 20 insertions account for up to 10% of all EGFR mutations. Clinical outcomes in patients receiving approved EGFR exon 20 insertion-specific inhibitors have been variable. Although osimertinib has demonstrated antitumor activity in clinical trials, its clinical efficacy and translational potential remain to be determined in non-small cell lung carcinoma (NSCLC) with EGFR exon 20 insertion. METHODS: In this multicenter phase II study, patients with advanced NSCLC harboring EGFR exon 20 insertions for whom the standard chemotherapy failed received 80 mg osimertinib once daily. The primary endpoint was the investigator-assessed objective response rate (ORR) as defined by Response Evaluation Criteria in Solid Tumors version 1.1. The secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety profile. RESULTS: Among 15 patients enrolled at stage 1, the best response was most commonly disease stabilization (73.3 %), which did not meet the stage 1 threshold (objective response ≥ 2/15). As of data cutoff, two patients remained on the treatment. The median PFS and OS were 3.8 (95 % confidence interval [CI] = 1.7-5.5) months and 6.5 (95 % CI = 3.9-not reached) months, respectively. Adverse events (≥grade 3) were anemia, hypercalcemia, and pneumonia (13.3 % each), and asthenia, femur fracture, increased alkaline phosphate, hyperkalemia, bone pain, and azotemia (6.7 % each). Pre-existing EGFR C797S mutation detected in plasma limited the efficacy of osimertinib. CONCLUSION: Osimertinib at 80 mg once daily had limited efficacy and mostly showed disease stabilization with an acceptable safety profile in advanced NSCLC harboring EGFR exon 20 insertions. CLINICALTRIALS: govIdentifier: NCT03414814.

Skeletal-Related Events in Patients With Multiple Myeloma: A Comprehensive Retrospective Cohort Study.

BACKGROUND: Multiple myeloma (MM) patients are at risk of skeletal-related events (SREs) like spinal cord compression, pathologic fractures, bone surgery, and radiation to bone. Real-world data regarding SREs in MM are limited. METHODS: We conducted a large, retrospective, nationwide cohort study using the Korean Health Insurance Review and Assessment Service (HIRA) database from 2007 to 2018. RESULTS: Over a 12-year study period, we identified 6,717 patients who developed symptomatic MM. After a median follow-up of 35.1 months (interquartile range [IQR], 20.8-58.2 months), 43.6% of these patients experienced SREs, and 39.6% had four or more SREs. One in five patients (20.0%) experienced pathologic fractures within the first year of follow-up. The median time to first SRE was 9.6 months (IQR, 1.2-25.8 months), with 3.0 months in the group with prior SREs and 19.8 months in the group without prior SREs. During follow-up, 78.5% of patients received bisphosphonates. Multiple logistic regression analysis revealed several factors associated with an increased risk of SREs, including being female (odds ratio [OR], 1.44), aged 50 or older (OR, 1.87), having cerebrovascular disease (OR, 1.34), undergoing first-line chemotherapy regimens not containing bortezomib or lenalidomide (OR, 1.49), and being in the group with prior SREs and bisphosphonate use (OR, 5.63), compared to the group without prior SREs and without bisphosphonate use. CONCLUSION: This population-based study is the first to report the incidence and risk factors of SREs in Korean MM patients, which can be used to assess their bone health.

Dimensionality Engineering of Magnetic Anisotropy from the Anomalous Hall Effect in Synthetic SrRuO3 Crystals.

Magnetic anisotropy in atomically thin correlated heterostructures is essential for exploring quantum magnetic phases for next-generation spintronics. Whereas previous studies have mostly focused on van der Waals systems, here we investigate the impact of dimensionality of epitaxially grown correlated oxides down to the monolayer limit on structural, magnetic, and orbital anisotropies. By designing oxide superlattices with a correlated ferromagnetic SrRuO3 and nonmagnetic SrTiO3 layers, we observed modulated ferromagnetic behavior with the change of the SrRuO3 thickness. Especially, for three-unit-cell-thick layers, we observe a significant 1500% improvement of the coercive field in the anomalous Hall effect, which cannot be solely attributed to the dimensional crossover in ferromagnetism. The atomic-scale heterostructures further reveal the systematic modulation of anisotropy for the lattice structure and orbital hybridization, explaining the enhanced magnetic anisotropy. Our findings provide valuable insights into engineering the anisotropic hybridization of synthetic magnetic crystals, offering a tunable spin order for various applications.

Amivantamab plus Lazertinib in Previously Untreated EGFR-Mutated Advanced NSCLC.

BACKGROUND: Amivantamab plus lazertinib (amivantamab-lazertinib) has shown clinically meaningful and durable antitumor activity in patients with previously untreated or osimertinib-pretreated EGFR (epidermal growth factor receptor)-mutated advanced non-small-cell lung cancer (NSCLC). METHODS: In a phase 3, international, randomized trial, we assigned, in a 2:2:1 ratio, patients with previously untreated EGFR-mutated (exon 19 deletion or L858R), locally advanced or metastatic NSCLC to receive amivantamab-lazertinib (in an open-label fashion), osimertinib (in a blinded fashion), or lazertinib (in a blinded fashion, to assess the contribution of treatment components). The primary end point was progression-free survival in the amivantamab-lazertinib group as compared with the osimertinib group, as assessed by blinded independent central review. RESULTS: Overall, 1074 patients underwent randomization (429 to amivantamab-lazertinib, 429 to osimertinib, and 216 to lazertinib). The median progression-free survival was significantly longer in the amivantamab-lazertinib group than in the osimertinib group (23.7 vs. 16.6 months; hazard ratio for disease progression or death, 0.70; 95% confidence interval [CI], 0.58 to 0.85; P<0.001). An objective response was observed in 86% of the patients (95% CI, 83 to 89) in the amivantamab-lazertinib group and in 85% of those (95% CI, 81 to 88) in the osimertinib group; among patients with a confirmed response (336 in the amivantamab-lazertinib group and 314 in the osimertinib group), the median response duration was 25.8 months (95% CI, 20.1 to could not be estimated) and 16.8 months (95% CI, 14.8 to 18.5), respectively. In a planned interim overall survival analysis of amivantamab-lazertinib as compared with osimertinib, the hazard ratio for death was 0.80 (95% CI, 0.61 to 1.05). Predominant adverse events were EGFR-related toxic effects. The incidence of discontinuation of all agents due to treatment-related adverse events was 10% with amivantamab-lazertinib and 3% with osimertinib. CONCLUSIONS: Amivantamab-lazertinib showed superior efficacy to osimertinib as first-line treatment in EGFR-mutated advanced NSCLC. (Funded by Janssen Research and Development; MARIPOSA ClinicalTrials.gov number, NCT04487080.).

Medium Chain Length Polyhydroxyalkanoate Production by Engineered Pseudomonas gessardii Using Acetate-formate as Carbon Sources.

Production of medium chain length polyhydroxyalkanoate (mcl-PHA) was attempted using Pseudomonas gessardii NIBRBAC000509957, which was isolated from Sunchang, Jeollabuk-do, Republic of Korea (35°24'27.7"N, 127°09'13.0"E) and effectively utilized acetate and formate as carbon sources. We first evaluated the utilization of acetate as a carbon source, revealing optimal growth at 5 g/L acetate. Then, formate was supplied to the acetate minimal medium as a carbon source to enhance cell growth. After overexpressing the acetate and formate assimilation pathway enzymes, this strain grew at a significantly higher rate in the medium. As this strain naturally produces PHA, it was further engineered metabolically to enhance mcl-PHA production. The engineered strain produced 0.40 g/L of mcl-PHA with a biomass content of 30.43% in fed-batch fermentation. Overall, this strain can be further developed to convert acetate and formate into valuable products.

Development of moyamoya arteriopathy following treatment of intracranial tumors: clinical and radiographic characterization.

OBJECTIVE: Moyamoya arteriopathy can develop in patients with brain tumors, particularly when associated with neurofibromatosis type 1 (NF1) or cranial irradiation. The present study aimed to analyze the clinical outcomes of moyamoya after brain tumor treatment and elucidate the effect of revascularization on brain tumors. METHODS: The authors retrospectively reviewed clinical and radiographic findings in 27 patients with brain tumors who developed moyamoya requiring revascularization surgery between January 1985 and June 2017 at a single institution. The long-term clinical and neuroimaging-based outcomes were analyzed. RESULTS: Among 27 patients, 22 patients underwent radiotherapy, and 12 patients had NF1. The mean ages at diagnosis of brain tumors and moyamoya were 4.4 years and 10.3 years, respectively. The mean interval between radiotherapy and moyamoya diagnosis was 4.0 years. The mean follow-up period after revascularization surgery was 8.5 years. Among 46 affected hemispheres in 27 patients, the patients who underwent radiotherapy (30 hemispheres in 22 patients) had a higher incidence of Suzuki stage 5 or 6 (20% [6/30] vs 0% [0/8]) and infarction (63.6% [14/22] vs 0% [0/5]) compared with patients without radiotherapy (8 hemispheres in 5 patients). After revascularization, stroke occurred in 4 patients, and 6 hemispheres showed Matsushima grade C, all of which occurred in patients with a history of radiotherapy. The residual brain tumors progressed in 4 of 21 patients (19%) after revascularization, comparable to the progression rates of brain tumors without revascularization in previous literature. CONCLUSIONS: Patients with brain tumors can develop moyamoya that exhibits characteristic clinical and radiographic features of idiopathic MMD. Moyamoya associated with cranial irradiation has a higher incidence of stroke with less capacity for revascularization, requiring thorough evaluations and timely treatment. Revascularization does not appear to have any effect on the progression of existing brain tumors.

Deterministic Orientation Control of Ferroelectric HfO2 Thin Film Growth by a Topotactic Phase Transition of an Oxide Electrode.

The scale-free ferroelectricity with superior Si compatibility of HfO2 has reawakened the feasibility of scaled-down nonvolatile devices and beyond the complementary metal-oxide-semiconductor (CMOS) architecture based on ferroelectric materials. However, despite the rapid development, fundamental understanding, and control of the metastable ferroelectric phase in terms of oxygen ion movement of HfO2 remain ambiguous. In this study, we have deterministically controlled the orientation of a single-crystalline ferroelectric phase HfO2 thin film via oxygen ion movement. We induced a topotactic phase transition of the metal electrode accompanied by the stabilization of the differently oriented ferroelectric phase HfO2 through the migration of oxygen ions between the oxygen-reactive metal electrode and the HfO2 layer. By stabilizing different polarization directions of HfO2 through oxygen ion migration, we can gain a profound understanding of the oxygen ion-relevant unclear phenomena of ferroelectric HfO2.