Abstract

PURPOSE: The NCCN guidelines recommend a chest computed tomography (CT) scan every 6 months for 2-3 years for patients with early-stage non-small cell lung cancer (NSCLC). This study aimed to evaluate whether multi-location CT scans offer a survival benefit.

MATERIALS AND METHODS: This study collected clinical data for NSCLC patients who underwent curative intent surgery between 2014 and 2018. Patients were grouped by surveillance CT type: chest CT only (Group CC) or combined chest-abdominal CT (Group CA). The primary outcomes include all-cause mortality, the risk of NSCLC recurrence, and the risk of developing a second primary cancer. Multivariable time-varying Cox models adjusted for clinical factors (age, sex, stage, hospital) and six covariates, including comorbidities, smoking, MVPA, CT frequency, time since surgery, and post-op cancer diagnosis.

RESULTS: Of 32,426 patients, 23,501 were analyzed after exclusions; 22,097 were in Group CC and 1,404 in Group CA. Group CC had a higher recurrence rate (18.7% vs. 14.4%), while Group CA had higher all-cause mortality (19.7% vs. 18.0%). Adjusted Cox analysis showed higher recurrence detection in Group CA (HR 1.80, 95% CI: 1.60-2.01) and lower mortality (HR 0.82, 95% CI: 0.71-0.94) vs. Group CC among patients with recurrence or second cancers. Subgroup analysis showed higher recurrence detection in Group CA for both stages. Mortality was reduced in regional stage (HR 0.77, 95% CI: 0.64-0.93), but not in local stage (HR 1.03, 95% CI: 0.78-1.35).

CONCLUSION: Multi-location CT surveillance after curative surgery in early-stage NSCLC, especially regional-stage, was associated with lower mortality, recurrence, and second primary cancer risk.

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BACKGROUND: Central nervous system (CNS) involvement remains a major cause of mortality in patients with epidermal growth factor receptor (EGFR)-mutated nonsmall cell lung cancer (NSCLC), particularly, after progression on EGFR tyrosine kinase inhibitors (TKIs). This pooled analysis evaluated the efficacy of lazertinib in patients with EGFR-mutated NSCLC and CNS involvement, using data from two Phase II trials.

PATIENTS AND METHODS: Patients with EGFR-mutated NSCLC and CNS involvement following prior EGFR TKI therapy enrolled in the KCSG-LU20-15 and KCSG-LU21-01 were included. Overall and intracranial objective response rate (ORR), disease control rate (DCR), and progression-free survival (PFS) were assessed.

RESULTS: Seventy-two patients were included. The median age was 63 years and 45 patients (62.5%) had leptomeningeal metastases (LM). T790M status was positive in 7 patients, negative in 44, and unknown in 21. Intracranial tumor responses were evaluable in 46 patients; the intracranial ORR was 50.0%, and the intracranial DCR was 97.8%. The median intracranial PFS was 15.2 months. Among 66 patients evaluable for systemic response, the overall ORR and DCR were 22.7% and 97.0%, respectively. The median PFS and overall survival were 10.6 and 17.8 months, respectively. Patients with LM experienced inferior OS and intracranial PFS compared with those without LM. No significant differences in clinical outcomes were observed according to T790M status.

CONCLUSION: Lazertinib demonstrated meaningful CNS activity in patients with EGFR-mutated NSCLC and CNS involvement after prior EGFR TKI exposure, including those with LM. Notably, this activity was observed in a cohort with a low prevalence of confirmed T790M positivity.

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Photomultiplication-type organic photodetectors (PM OPDs), which rely on signal amplification via electron trapping, suffer from a fundamental trade-off: high gain is typically accompanied by a steep increase in dark current under high reverse bias. Here, we overcome this challenge by employing ionic conjugated polyelectrolyte (CPE)-based electron blocking layers (EBLs) with an alternating fluorene-co-triphenylamine backbone. CPE-based EBLs in PM OPDs enable robust dark current stability under reverse bias up to -10 V while maintaining external quantum efficiencies (EQE) exceeding 2000%. Charge-dynamics analysis using Fowler-Nordheim plots reveals that a nanometer-thick CPE layer provides electron-blocking performance comparable to that of a ∼20 nm Al2O3 layer. At the same time, we show that the nature of the ionic side chains (cationic vs anionic) in CPEs governs interfacial energy-level alignment, thereby modulating hole selectivity and photocarrier dynamics. The design principles establish a general framework for interfacial and field engineering across a broad range of photodetector platforms-from organic to hybrid systems-guiding the development of next-generation photodetectors.

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PURPOSE: We assessed whether baseline and early on-treatment measurements of host fitness using the Prognostic Nutritional Index (PNI) provide complementary prognostic information in advanced non-small cell lung cancer (NSCLC).

MATERIALS AND METHODS: Within the prospective, multicenter OPTIMUS trial, 497 patients with advanced NSCLC receiving first-line pembrolizumab-based therapy were analyzed. PNI was calculated from serum albumin and lymphocyte count at baseline and before cycle 2 (early on-treatment). Using a cutoff of 50.5, 441 patients with paired measurements were classified by baseline/early on-treatment PNI status as high/high, high/low, low/high, or low/low.

RESULTS: Low baseline PNI was associated with lower objective response and higher treatment-related mortality. Among responders, low early on-treatment PNI was associated with lower odds of 6-month response maintenance (adjusted OR, 0.40; 95% CI, 0.17-0.97). Response-maintenance rates were lowest in the low/low group at both 6 and 12 months. In multivariable analyses including both PNI time points, low early on-treatment PNI was associated with shorter PFS (HR, 1.50; 95% CI, 1.11-2.04), whereas low baseline PNI was not (HR, 1.27; 95% CI, 0.94-1.71). Both low baseline PNI (HR, 1.53; 95% CI, 1.07-2.19) and low early on-treatment PNI (HR, 1.47; 95% CI, 1.02-2.12) were associated with shorter OS. The higher mortality risk in the low/low group was generally consistent across PD-L1 expression and treatment regimen subgroups.

CONCLUSION: PNI assessment at baseline and before cycle 2 provides complementary prognostic information, with early on-treatment PNI particularly related to PFS and response durability (ClinicalTrials.gov Identifier: NCT04909164).

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PURPOSE: Epidermal growth factor receptor (EGFR) amplification remains a controversial therapeutic biomarker. We report outcomes of erlotinib plus bevacizumab (E + B) in patients with EGFR-amplified metastatic solid tumors.

METHODS: Patients with metastatic solid cancer who had progressed after standard therapies and were treated with E + B based on central molecular tumor board recommendations in the KOSMOS trial were included. Only those with an EGFR copy number ≥ 3 were selected. The primary endpoint was the clinical benefit rate (CBR), while secondary endpoints included overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety.

RESULTS: Between February 2021 and April 2024, 25 patients were treated with E + B (median EGFR copy 8.9; range, 3-76). Six tumor types were included, with colorectal cancer being the most prevalent (N = 14), followed by glioblastoma (N = 5), and other types (N = 6). Overall, four partial responses (PR) and seven cases of stable disease (SD) lasting over 16 weeks were observed, resulting in a CBR of 44.0% and ORR of 16%. The median PFS was 3.7 months (95% confidence interval [CI]: 1.7-4.6), whereas the median OS was 7.9 months (95% CI: 6.5 to not estimable). Six patients experienced one or more grade 3 adverse events related to E + B, including hypertension and mucositis.

CONCLUSION: The E + B combination showed modest anti-tumor activity in patients with heavily pretreated EGFR-amplified solid cancers. While NGS may help identify new applications for existing drugs, additional investigations are warranted to validate the efficacy and benefit of E + B in this population.

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We examined treatment patterns and overall survival (OS) among patients with small-cell lung cancer (SCLC) in South Korea. This retrospective cohort study included patients with SCLC treated at Samsung Medical Center between January 1, 2018 and December 31, 2021, with follow-up through March 13, 2023. The first systemic therapy after initial diagnosis was defined as first-line, with subsequent lines identified by initiation of new regimens. Survival outcomes were estimated from the start of each treatment line. Among 515 patients, 343 had extensive-stage (ES) and 172 had limited-stage (LS) at diagnosis. Platinum-based regimen without anti-PD-L1 was the most common first-line regimen for both groups; however, use of anti-PD-L1 containing platinum regimens increased markedly from 2020 onward in patients with ES-SCLC. In the second line setting, 64% of patients with ES-SCLC received platinum-based therapy and 31% irinotecan monotherapy, whereas taxanes were predominantly used in patients with LS-SCLC (51.7%). Median OS for ES-SCLC following first-line treatment was 11.3 months (95% CI: 9.7, 12.2) [11.4 months (95% CI: 9.6, 12.8) with anti-PD-L1 vs. 11.1 months (95% CI: 9.2, 12.5) without], and 29.8 months (95% CI: 23.6, 46.6) months following first definitive therapy for LS-SCLC. Median OS declined to 6.9 months (95% CI: 6.3, 7.9) after second line therapy in ES-SCLC and 12.1 months (95% CI: 7.9, 17.1) in patients with LS-SCLC following 1L therapy after initial definitive therapy. These findings characterize the evolving SCLC treatment landscape, underscore the limited effectiveness of current treatment options, and highlight the persistent poor prognosis in this population.

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Sotos syndrome is an overgrowth disorder caused by nuclear receptor binding SET domain protein 1 (NSD1) haploinsufficiency, whereas reciprocal 5q35.2q35.3 microduplication produces a reversed phenotype with growth retardation, microcephaly, delayed bone age, and neurodevelopmental delay. We describe a 43-month-old Korean girl born at 36 + 1 weeks with intrauterine growth restriction (birth weight 2200 g, length 46 cm, occipitofrontal circumference 42 cm). At presentation, all growth parameters were below the 10th percentile, with dysmorphic features including epicanthal folds, telecanthus, and a wide nasal bridge. She walked at 14 months but had an approximately 25-month language delay. Chromosomal microarray revealed a de novo 1.8 Mb duplication at 5q35.2q35.3 encompassing NSD1, classified as pathogenic (triplosensitivity score 3). A growth hormone (GH) stimulation test confirmed deficiency (peak GH 9.87 and 6.42 ng/mL). Recombinant human GH therapy (0.033 mg/kg/day) improved growth to the 5-10th percentile after 6 months. This is the first reported Korean case of 5q35.2q35.3 duplication with reversed Sotos phenotype and GH deficiency, which expands the endocrine spectrum of the disorder and underscores the need for early genetic testing and endocrine evaluation. [Correction added after first online publication on 23 March 2026: The dosage of rGH therapy was corrected from "0.1 IU/kg/day" to "0.033 mg/kg/day.].

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Inverted perovskite solar cells (PeSCs) have attracted growing attention, due to their low-temperature processability, reduced hysteresis, and strong compatibility with flexible and tandem device architectures, and have now surpassed conventional devices in terms of both power conversion efficiency and operational stability. Despite these advantages, their long-term operational stability remains critically constrained by the upper device stack, spanning from the perovskite surface through the electron-transporting layer (ETL) to the metal cathode. This review systematically analyzes the dominant origins of instability at these top interfaces in inverted PeSCs and organizes recent progress into three key design directions: (i) perovskite/ETL interface engineering using organic and inorganic modifiers, low-dimensional perovskite capping layers, and thermally conductive interlayers; (ii) C60 replacements or non-fullerene ETLs that integrate defect passivation, interfacial dipole tuning, ion management, and aggregation-resistant morphologies; and (iii) ETL/cathode interlayers that regulate band bending, suppress interfacial recombination, and block volatile halide migration. Finally, the Outlook section discusses emerging opportunities and remaining challenges in further optimizing ETLs and top interlayers, with particular emphasis on advancing the operational stability and commercial viability of inverted PeSCs and their integration into high-performance tandem solar cells.

Abstract

In the original publication [...].

Abstract

PURPOSE: This study evaluated the feasibility of involved-field irradiation (IFI) with a small margin (SM) in patients with esophageal squamous cell carcinoma (ESCC) undergoing neoadjuvant chemoradiotherapy.

METHODS AND MATERIALS: We retrospectively reviewed 511 patients with ESCC who underwent neoadjuvant chemoradiation therapy followed by radical esophagectomy between 2016 and 2022. The IFI was routinely applied. The clinical target volume was defined as the primary gross tumor volume plus a 2.0 to 3.0 cm longitudinal and 0.5 to 1.0 cm circumferential margin, and the nodal gross tumor volume plus a 0.5 to 1.0 cm margin, with modifications. Patients receiving a 2 cm longitudinal margin without further extension were classified as the SM group (n = 366); the others comprised the large-margin group. With radical esophagectomy, 3-field lymph node (LN) dissection was performed in 212 patients (41.5%), whereas 296 patients (57.9%) underwent 2-field LN dissection. Failure patterns, locoregional control, and survival outcomes were analyzed. Regional recurrence included LN defined by the American Joint Committee on Cancer eighth edition and supraclavicular nodes.

RESULTS: During the median follow-up of 44.8 months, 213 patients (41.7%) experienced recurrence. First recurrences were locoregional recurrence (LRR) in 120 (23.5%), nonregional LN in 56 (11.0%), and distant metastases in 153 (29.9%) patients. Among LRR cases, 52 patients (10.2%) had infield failures, 28 (5.5%) had both infield and outfield failures, and 40 (7.8%) had outfield failures. Isolated outfield LRR occurred in only 17 patients (3.3%), of whom only 4 would have had their lesions covered by elective nodal irradiation. Locoregional control, progression-free survival, and overall survival did not differ between the SM and large-margin groups.

CONCLUSIONS: IFI with SM demonstrated favorable outcomes and minimal isolated outfield recurrence, supporting its feasibility as a neoadjuvant setting for ESCC.

Abstract

PURPOSE: This study investigated whether the benefit of patients with recurrent and/or metastatic nasopharyngeal carcinoma (R/M NPC) from immune checkpoint inhibitor (ICI)-containing regimens was correlated with the presence of tumor microenvironment (TME) cell subpopulations that correlate with clinical outcomes.

PATIENTS AND METHODS: A total of 73 patients with R/M NPC from four prospective trials in three centers using nivolumab monotherapy, nivolumab + gemcitabine, nivolumab + ipilimumab, or avelumab + axitinib were included. Lunit SCOPE IO, an artificial intelligence-powered spatial TME analyzer, analyzed tumor-infiltrating lymphocytes (TILs), macrophages (MPs), fibroblasts (FBs), and endothelial cells in the intratumoral area and adjacent stroma.

RESULTS: The median progression-free survival (PFS) was 7.3 months, and the median overall survival (OS) was 30.0 months for the entire cohort. Higher intratumoral immune infiltrates showed association with improved treatment response, with both intratumoral TILs (hazard ratio [HR], 0.44 [95% CI, 0.24 to 0.83]; P = .0081) and intratumoral MPs (HR, 0.5 [95% CI, 0.27 to 0.91]; P = .0209) showing associations with improved PFS in the combined cohort. In contrast, stromal immune populations did not show clear correlations (stromal TILs: HR 1.14, P = .6681; stromal MPs: HR 0.9, P = .7278). Higher stromal FB density was also associated with poor outcomes, showing a trend toward shorter PFS and a significant reduction in OS (HR, 2.44 [95% CI, 1.16 to 5.11]; P < .05).

CONCLUSION: The results from this multinational cohort suggest that high intratumoral infiltrations of TILs and MPs, along with low stromal FB densities, may be associated with better response to ICI-containing treatment in NPC. Further studies in larger, expanded cohorts are warranted, and prospective validation is needed.

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PURPOSE: Alectinib has been approved for anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) at 300 mg twice daily in Japan, lower than global standard of 600 mg twice daily. This study evaluated the clinical relevance of the reduced dose by comparing outcomes between the two doses.

MATERIALS AND METHODS: This study included patients with advanced ALK-positive NSCLC who received alectinib at Samsung Medical Center, Korea. The progression-free survival (PFS), overall survival, cumulative incidence of central nervous system (CNS) progression, and safety profiles were retrospectively reviewed and compared.

RESULTS: Among 306 patients, 32 and 274 received alectinib at either 300 or 600 mg twice daily, respectively. The 300 mg group showed a slight but not significant advantage in PFS (hazard ratio [HR], 0.82; 95% confidence interval [CI], 0.44 to 1.51; p=0.51) and overall survival (HR, 0.51; 95% CI, 0.20 to 1.21; p=0.13). Superior outcome with 300 mg was remarkable in patients with lower body weight (≤ 60 kg), but diminished in patients with higher body weights. Patients with baseline brain metastasis in the 300 mg group exhibited a slight increase in incidence of CNS failure (HR, 1.76; 95% CI, 0.53 to 5.8; p=0.36). Although the safety profiles were mostly mild, adverse events were more frequent in the 600 mg group, 50% of which requiring dose reduction.

CONCLUSION: Alectinib at 300 mg twice daily seems an acceptable dose in East Asians with ALK-positive NSCLC. Notably, our data favor 300 mg twice daily in patients with lower body weight and no baseline brain metastasis, considering the more tolerable safety profiles and the potential to reduce medical costs.

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PURPOSE: Brain metastases are a serious complication in non-small cell lung cancer (NSCLC). However, data regarding efficacy of immune checkpoint inhibitors and chemotherapy combinations are limited. This phase II study aimed to evaluate the intracranial efficacy and safety of pembrolizumab and chemotherapy in treatment-naïve NSCLC patients with asymptomatic brain metastases.

MATERIALS AND METHODS: This single-arm, phase II trial was conducted at Samsung Medical Center, Korea. Eligible patients had stage IV NSCLC with asymptomatic, untreated brain metastases and no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) alterations. Patients received pembrolizumab with chemotherapy every 3 weeks for 4 cycles, followed by pembrolizumab with or without maintenance chemotherapy up to 35 cycles. The primary endpoint was intracranial objective response rate (icORR). Secondary endpoints included intracranial progression free survival (icPFS), intracranial duration of response (icDoR), objective response rate (ORR), progression free survival (PFS), overall survival, and safety.

RESULTS: Between February 2021 and June 2024, a total of 13 patients were enrolled. Due to challenges in recruiting patients, enrollment was discontinued after the 13 patients. The icORR was 46.2% (95% CI, 19.2-74.8), with 6 patients achieving partial response. The median icPFS was 9.8 months (95% CI, 5.2-21.5), and median icDoR was 9.3 months (95% CI, 4.0-20.3). Median PFS and overall survival was 7.2 months (95% CI, 2.4-12.3) and 10.7 months (95% CI, 7.2-21.5), respectively. Most treatment-related adverse events were grade 1-2."

CONCLUSION: Pembrolizumab combined with chemotherapy demonstrated encouraging intracranial activity and manageable safety profile in NSCLC patients with untreated, asymptomatic brain metastases.

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BACKGROUND: The treatment landscape for metastatic or advanced non-small cell lung cancer (aNSCLC) evolved with the development of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs). However, EGFR exon 20 insertion (E20ins) mutations remain challenging to target. This study delineates molecular epidemiology, clinical characteristics, treatments, and survival outcomes of patients with E20ins compared to other EGFR mutations.

METHODS: Electronic medical records (EMRs) from three major hospitals in South Korea were analyzed retrospectively. Patients diagnosed with aNSCLC and confirmed EGFR mutations between 2014 and 2019 were included. Demographics, clinical characteristics, and treatment outcomes were analyzed to compare the impact of different EGFR mutations on patient outcomes.

RESULTS: Among 2,209 patients with aNSCLC, 1,978 (89.5%) exhibited common EGFR mutations [exon 19 deletion (E19del) and a single point mutation from leucine to arginine at exon 21 (E21L858R)], and 53 (2.4%) had E20ins. E20ins patients demonstrated notably poorer survival outcomes, with median overall survival (OS) of 13.9 months [95% confidence interval (CI): 10.1-not reached] compared to 31.0 months (95% CI: 29.0-35.8) for those with common mutations. Among 810 aNSCLC patients tested by both next-generation sequencing (NGS) and polymerase chain reaction (PCR), 21 were positive for E20ins by NGS, and 13 were positive by PCR. Of the 21 E20ins positives detected by NGS, 10 (47.6%) were not detected by PCR, while 2 patients (0.3%) were only positive for E20ins by PCR.

CONCLUSIONS: E20ins represents a small but significant subset of EGFR mutations in aNSCLC, with worse survival outcomes. The study also highlighted superior sensitivity of NGS over PCR in detecting E20ins. This underscores necessity for improved detection strategies and effective treatments tailored to this mutation subgroup.

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BACKGROUND: Head and neck squamous-cell carcinoma (HNSCC) accounts for ∼5.3% of cancer-related mortality worldwide, with an estimated 890 000 new diagnoses and 450 000 deaths annually. Despite curative-intent therapy, 10% to 50% of patients experience recurrence. Prognosis for recurrent or metastatic disease is poor, with limited treatment options, underscoring the need for accurate prognostic models to guide treatment escalation or de-escalation and avoid over-treatment.

METHODS: We conducted a multicenter prognostic study of patients undergoing curative-intent surgery at Samsung Medical Center and Massachusetts Eye and Ear Infirmary/Massachusetts General Hospital from 2008 to 2024. Baseline clinicopathologic variables were integrated with longitudinal laboratory measurements from surveillance. A random 80/20 split defined development and internal-validation cohorts. Using XGBoost, we trained two models to predict recurrence-free survival (RFS) and overall survival (OS) at 1, 2, 3, 4, and 5 years from each visit.

RESULTS: A total of 975 patients with HNSCC (oral cavity, oropharyngeal, hypopharyngeal, and laryngeal subsites) were included. The areas under the curve (AUCs) for predicting 1-, 2-, 3-, 4-, and 5-year RFS from the surveillance time point were 0.785 (sensitivity, 72.8%; specificity, 71.5%), 0.831 (79.7%; 73.7%), 0.788 (74.0%; 73.3%), 0.769 (72.6%; 70.5%), and 0.795 (72.1%; 74.7%), respectively. For OS prediction, AUCs were 0.788 (72.1%; 73.6%), 0.797 (75.7%; 71.8%), 0.796 (81.0%; 68.4%), 0.820 (77.5%; 76.5%), and 0.815 (75.8%; 75.8%), respectively. In subgroup analysis, the model showed strong OS prediction in human papilloma virus (HPV)-positive oropharyngeal cancer, with AUCs of 0.943, 0.736, 0.699, 0.835, and 0.765 at 1-, 2-, 3-, 4-, and 5-years, respectively. In non-HPV-positive HNSCC, OS AUCs ranged from 0.780 to 0.813 and RFS AUCs from 0.774 to 0.830 across the same time points.

CONCLUSIONS AND RELEVANCE: In this multicenter study, an artificial intelligence (AI)-powered model using multimodal and longitudinal data accurately predicted RFS and OS at multiple time points following curative-intent surgery for HNSCC.

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BACKGROUND: APOBEC plays a crucial role in the mutation process and immune response of non-small cell lung cancer (NSCLC). This study evaluated the role of the APOBEC mutation signature in early-stage epidermal growth factor receptor (EGFR) mutant NSCLC. This study aimed to assess the impact of APOBEC enrichment on recurrence-free survival (RFS), post-recurrence tyrosine kinase inhibitor (TKI) progression-free survival (PFS), and post-recurrence survival (PRS).

METHODS: We conducted whole-exome sequencing and whole-transcriptome sequencing in 100 patients diagnosed with pathologic stage II-IIIA non-squamous NSCLC.

RESULTS: Among the 100 patients, 18 (18 %) exhibited APOBEC (≥2) enrichment, which did not show a significant association with RFS (P = 0.14). Patients with APOBEC enrichment showed a shorter post-recurrence TKI PFS compared to those without APOBEC enrichment (8.13 months vs. 24.57 months, P = 0.017). In multivariate analysis, poor post-recurrence TKI PFS was associated with the type of EGFR mutation (L858R vs. exon 19 deletion, HR = 1.91, P = 0.04), TP53 mutation (HR = 2.07, P = 0.03), and APOBEC enrichment (≥2 vs. < 2, HR = 2.23, P = 0.02). PRS was 61.10 months and 21.77 months for patients with APOBEC enrichment and patients without APOBEC enrichment, respectively (P = 0.029). In multivariate analysis, poor PRS of EGFR-TKI was associated with the type of EGFR mutation (L858R vs. exon 19 deletion, HR = 2.29, P = 0.04) and APOBEC enrichment (≥2 vs. < 2, HR = 2.71, P = 0.02).

CONCLUSIONS: APOBEC enrichment may present at initial diagnosis of early-stage EGFR mutant NSCLC and is associated with poor post-recurrence TKI PFS and PRS rather than RFS.

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BACKGROUND: Tepotinib received Food and Drug Administration approval for advanced non-small cell lung cancer (aNSCLC) with MET exon 14 skipping mutation (METex14m) based on a single-arm trial. However, the comparative effectiveness between tepotinib and standard of care (SoC) remains unclear.

OBJECTIVES: We aim to assess the long-term comparative effectiveness between first-line tepotinib and SoC.

DESIGN: This retrospective comparative effectiveness study was conducted based on a matching-adjusted indirect comparison using aggregate data for Asian patients of the VISION trial for the tepotinib arm, and data of patients with METex14m who received SoC from Samsung Medical Center data in January 2008 and February 2024 for the SoC arm.

METHODS: Hazard ratio (HR) and its confidence intervals (CIs) for progression-free survival (PFS) and overall survival (OS) were assessed through a Cox proportional hazards model. A partitioned survival model was run for a lifetime using four different scenarios to estimate long-term quality-adjusted life-years (QALYs), which reflect patients' health-related quality of life (HRQoL).

RESULTS: In the SoC arm (n = 44), 26 and 18 were treated with an immunotherapy-containing regimen and chemotherapy, as their first-line SoC. Thirty (68.2%) of the SoC (n = 44) arm received subsequent METex14-targeting therapy. Tepotinib significantly improved PFS compared to SoC (HR (95% CI), 0.38 (0.22-0.63)). The PFS improvement was more pronounced when compared to the chemotherapy subgroup (HR (95% CI), 0.20 (0.10-0.38)) and was also evident in the immunotherapy-containing regimen subgroup (HR (95% CI), 0.55 (0.29-1.03)). Although OS did not differ significantly (HR (95% CI), 1.04 (0.56-1.93)), the partitioned survival model yielded an additional 0.2409-0.3039 QALYs in the tepotinib arm, showing HRQoL benefits of tepotinib over SoC.

CONCLUSION: The significant PFS benefit of first-line tepotinib over SoC extended to long-term HRQoL gains, indicating tepotinib is considered one of the first-line treatment options. Future studies based on multicenter data or head-to-head trials would be able to verify the efficacy.

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BACKGROUND: Epidermal growth factor receptor (EGFR) exon 20 insertion mutations in non-small cell lung cancer (NSCLC) represent a distinct molecular subset with limited response to conventional tyrosine kinase inhibitors (TKIs). Mobocertinib, a targeted EGFR exon 20 inhibitor, shows clinical activity, yet the genomic resistance mechanisms remain poorly characterized, particularly through circulating tumor DNA (ctDNA) analysis.

METHODS: In this single-center prospective observational study, 22 patients with EGFR exon 20 insertion-positive NSCLC treated with mobocertinib were analyzed. Clinical outcomes were evaluated using Response Evaluation Criteria for Solid Tumors v1.1. Paired circulating tumor DNA (ctDNA) sequencing was performed pre- and post-treatment to characterize baseline mutations and acquired resistance mechanisms.

RESULTS: Mobocertinib achieved an objective response rate (ORR) of 59% and a disease control rate (DCR) of 82%, with a median progression-free survival (PFS) of 5.6 months (95% CI 3.5-9.3). Subjects who previously received amivantamab (n = 14) showed an ORR of 57.1% with median duration of response and PFS of 5.1 and 5.8 months, respectively. Insertion site variability influenced treatment efficacy, with better responses observed in helical region insertions. Baseline ctDNA absence correlated with favorable outcomes and ATM alterations emerged as potential negative predictive biomarkers. Resistance mechanisms were diverse, including EGFR amplification, RTK/RAS pathway alterations, and rare events such as gene fusion and small-cell lung cancer transformation.

CONCLUSIONS: Mobocertinib demonstrated clinically meaningful activity, regardless of previous exposure to amivantamab, in EGFR exon 20 insertion-positive NSCLC subjects. Acquired resistance mechanisms to mobocertinib were diverse, which poses challenges to sustained efficacy, emphasizing the need for development of a tailored subsequent therapeutic strategy.

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Nerve growth factor (NGF) binding to the receptor tyrosine kinase, TrkA, drives neurotrophic signaling essential for neuronal development and survival. This interaction simultaneously drives peripheral pain, making this pathway an attractive but complicated therapeutic target for chronic pain. By integrating single-molecule microscopy, structural and electrophysiology analyses, with a human NGF variant, NGF painless , which retains neurotrophic effects but abolishes pain, we delineate the molecular mechanisms that bias TrkA signaling towards neurotrophic functions without triggering nociception. We show that, unlike wild-type NGF, NGF painless fails to sensitize TRPV1 channels to capsaicin, thus disengaging TrkA from the nociceptive pathway. We further show that this selective loss of nociceptive TrkA signaling by NGF painless results from its reduced ability to activate PLCγ1 and trigger calcium release compared to NGF, while still preserving the ERK and AKT signaling essential for neurotrophic functions. This biased signaling arises from reduced electrostatic complementarity at the TrkA:NGF painless complex interface, which shortens the lifetime of this functional complex on native membranes. Mutations in TrkA that restore the electrostatic complementarity at the TrkA:NGF painless interface eliminate biased signaling. This mechanistic understanding of TrkA binding by NGF painless , and how it differs from NGF, will spur the development of two therapeutic classes of molecules - one that selectively suppresses nociceptive signaling while preserving neurotrophic functions in chronic pain, and another that enhances neurotrophic activity without evoking peripheral pain in neurodegenerative conditions.

Abstract

PURPOSE: Lazertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, has demonstrated high blood-brain barrier (BBB) penetration in preclinical studies. Similarly, pemetrexed has shown effective BBB penetration and survival benefit in EGFR-mutant non-small cell lung cancer (NSCLC) with leptomeningeal carcinomatosis (LM). This study evaluated the efficacy and safety of lazertinib plus pemetrexed in patients with EGFR-mutant NSCLC and LM.

METHODS: This prospective, phase II, single-arm, multi-center study enrolled patients with NSCLC and EGFR mutations and cytologically confirmed LM across six hospitals in Korea. Patients received lazertinib (240 mg daily) and pemetrexed (500 mg/m2 every three weeks). The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), cerebrospinal fluid (CSF) cytology conversion rate, quality of life, and safety. Pharmacokinetics were evaluated through CSF and plasma sampling.

RESULTS: Among 36 patients treated with lazertinib plus pemetrexed, the overall response and disease control rates were 24.1 % and 96.6 %, respectively. Median PFS and OS were 9.3 and 9.9 months, respectively. CSF cytology conversion rates were 9.4 % and 11.5 % at the second and third cycles, respectively. OS and CSF/plasma concentration ratios demonstrated significant correlation in cycle 3. Adverse events occurred in 66.7 % of patients, with peripheral neuropathy (33.3 %) and cutaneous reactions (33.3 %) being the most common. Significant improvements in quality of life and neurological symptoms were noted.

CONCLUSIONS: Lazertinib plus pemetrexed demonstrated promising intracranial efficacy, OS benefits, and improved quality of life, highlighting its potential as a treatment option for EGFR-mutant NSCLC and LM, particularly in previously treated patients.

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INTRODUCTION: Complete surgical resection remains the only potentially curative option for thymic epithelial tumors (TETs). We hypothesized that adding perioperative pembrolizumab to standard therapy may improve response, resectability, and disease-free survival (DFS).

METHODS: In this single-arm, prospective phase 2 trial, patients with potentially resectable TETs (Masaoka-Koga stages III-IV) received neoadjuvant docetaxel (75 mg/m2), cisplatin (75 mg/m2), and pembrolizumab (200 mg) every 3 weeks for 3 cycles, followed by surgery and maintenance pembrolizumab for 2 years. R1/R2-resected patients received adjuvant radiotherapy concomitant with pembrolizumab. The primary end point was a major pathologic response (MPR).

RESULTS: From March 2020 to January 2025, 40 untreated patients were recruited, including those with WHO B3 thymoma (n = 7, 17.5%) or thymic carcinoma (n = 29, 72.5%). Most were diagnosed with stage IV disease (n = 31, 77.5%). The median follow-up duration was 27.5 months (95% confidence interval [CI]: 22.0-39.2), and 28 patients (70.0%) underwent surgical resection. Among the patients who received surgery, MPR and pathologic complete response were observed in 13 (46.4%) and five (17.9%) patients, respectively. Notably, all cases of MPR and pathologic complete response occurred exclusively in patients with thymic carcinoma, not in those with thymoma. The 1-year DFS rate was 91.0% (95% CI: 79.9-100.0), and the median DFS was 49.3 months (95% CI: 25.3-not reached) from the time point of surgery. Most of the adverse events were grade 1 or 2 (n = 21, 52.5%), with nine (22.5%) grade 3 and five (12.5%) grade 4. Two patients with thymoma died from myocarditis.

CONCLUSIONS: Perioperative pembrolizumab demonstrated promising rates of MPR, R0 resection, and long-term DFS in stage III to IV TETs.

CLINICAL TRIAL REGISTRATION: NCT03858582 (MK3475-971).

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BACKGROUND: In the lack of head-to-head trials comparing lorlatinib and alectinib, we aimed to assess the effectiveness of lorlatinib versus alectinib as first-line treatment for advanced ALK-rearranged non-small cell lung cancer (NSCLC), with a focus on Asian population.

METHODS: In this comparative effectiveness study, the data on the lorlatinib group were obtained from the CROWN trial. Following the CROWN trial's inclusion criteria, real-world adult patients with advanced ALK-rearranged NSCLC who received first-line alectinib between January 1, 2017 and February 27, 2024, from the Samsung Medical Center were included in the alectinib group. Using matching-adjusted indirect comparison (MAIC), hazard ratios (HRs) and their 95 % confidence intervals (CIs) for overall survival (OS), progression-free survival (PFS), and intracranial (IC)-PFS were evaluated based on Cox proportional hazard models.

RESULTS: A total of 223 patients were included in the alectinib group with effective sample size of 90.2 and 178.1 after MAIC against the overall (multiracial) and Asian populations in the CROWN trial, respectively. Compared to the multiracial population, OS (HR, 1.52; 95 % CI, 0.77-2.99) and PFS (HR, 1.03; 95 % CI, 0.67-1.59) were not significantly different between the alectinib and lorlatinib groups. Consistently, PFS and OS of the alectinib group were not significantly different from those of the Asian lorlatinib group (HR, 1.31; 95 % CI, 0.80-2.14). IC-PFS was not significantly different between the two drugs, regardless of race.

CONCLUSIONS: First-line lorlatinib showed comparable efficacy to alectinib especially in Asian population. Further long-term and race-specific data are needed to guide more precise treatment decisions.

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IMPORTANCE: Head and neck squamous cell carcinoma (HNSCC) represents a significant global health burden with limited therapeutic options for patients with recurrent or metastatic disease. Epidermal growth factor receptor (EGFR) is overexpressed in most patients with HNSCC and represents a biologically compelling target, yet current EGFR-directed therapies have demonstrated only modest clinical benefit.

OBSERVATIONS: This review describes the evolving landscape of EGFR-targeted therapeutics in HNSCC, including cetuximab-based combination regimens as well as novel agents, such as bispecific antibodies, antibody-drug conjugates, immune cell engagers, and adaptive cell therapies. The biological rationale behind these approaches, and the results of early-phase trials, are presented in this review. Notably, cetuximab and other EGFR-targeted therapies have demonstrated inferior efficacy in patients with human papillomavirus (HPV)-positive disease.

CONCLUSIONS AND RELEVANCE: The emerging data of combinatorial approaches and novel EGFR-targeting therapeutic agents offer renewed optimism for patients with advanced HNSCC who have limited treatment options. Future progress will depend on novel agents leveraging a deeper understanding of tumor biology, innovative approaches to reduce on-target off-tumor toxic effects of targeting EGFR, and improving efficacy in the growing population of patients with HPV-positive HNSCC.

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Acanthopanax sessiliflorus, belonging to the Araliaceae family, is used as medicinal herbs and dietary supplements, and can be consumed as seasoned vegetables, salads, pickles, functional tea, and wine. Their edible parts (shoots, leaves, fruis, and stems) are considered as a highly valuable food source with health benefits. The comparison of the qualitative and quantitative characteristics of functional compounds in these plant parts is still limited. This study characterized phenolic compounds and triterpenoid saponins in the shoots, leaves, fruits, and stems using UPLC-MS and multivariate analyses. 116 compounds were investigated, with 36 compounds reported for the first time in the Acanthopanax genus. The contents of 19 target compounds including chiisanoside and quercetin 3-O-glucuronide were compared, and 57 chemical markers were identified through PLS-DA analysis. 3,4-Seco-lupane-type saponins were mainly found in the shoots and leaves, whereas oleanane-type saponins were mainly present in the stems and fruits. Lignans were identified as chemical markers in the stems, while feruloylquinic acid derivatives and flavonoids (taxifolin and cyanidin glycosides) were distinctively found in the fruits. These findings provide valuable insight into phytochemical profile of the species, which may be utilized in functional food development, rapid differentiation from other plants, and applications in related fields.

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PURPOSE: This study evaluated the dynamic changes in the tumor microenvironment (TME) in patients with non-small cell lung cancer (NSCLC) and acquired resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) using an artificial intelligence (AI)-powered spatial TME analyzer. We then assessed the predictive efficacy of immune-checkpoint inhibitors (ICIs)-based treatment.

EXPERIMENTAL DESIGN: An AI-powered whole-slide image analyzer was used to segment cancer areas (CAs) and cancer stroma and to identify tumor-infiltrating lymphocytes (TILs), tertiary lymphoid structures, fibroblasts, and endothelial cells (ECs) in the tumor tissue. We analyzed 143 NSCLC samples after resistance to EGFR-TKIs from two cohorts: (1) 89 patients treated with ICI monotherapy and (2) 54 patients from the ATTLAS phase III trial comparing atezolizumab plus bevacizumab, paclitaxel, and carboplatin (ABCP) versus pemetrexed plus carboplatin.

RESULTS: Post-TKI samples showed reduced TILs in the CA (p=0.045) and increased ECs in the CA (p=0.005) compared with pre-TKI samples. These changes differed according to EGFR mutation subtype. Higher TILs in CA were associated with a better overall response rate (ORR) and progression-free survival (PFS). Similarly, higher EC levels in CA correlated with improved ORR and PFS. In the ATTLAS cohort, these factors were associated with clinical benefits from ABCP, with a significant association with TILs and a marginal association with ECs.

CONCLUSION: Our findings suggest that EGFR-TKIs affect the immune landscape of patients with EGFR-mutated NSCLC. Higher TILs or ECs in the CA were significantly associated with a favorable response to subsequent ICI-based treatment.

TRIAL REGISTRATION NUMBER: NCT03991403.

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BACKGROUND: Discoveries of actionable gene alterations (AGAs) have driven significant advances in targeted therapies, enhancing survival for non-small cell lung cancer (NSCLC) patients. In cases of AGAs other than common EGFR, ALK, and ROS1 mutations, target therapies have various strengths of the recommendation depending on their previous studies. Meanwhile, the immune checkpoint inhibitors (ICIs) combined with chemotherapy is still widely used as a first-line treatment for most of NSCLC with AGAs due to limited accessibility of target therapy.

METHODS: This study included patients with NSCLC harboring AGAs who received chemotherapy plus ICIs (CT + IO) or chemotherapy alone (CT) as a first-line treatment between January 2019 and May 2023 at Samsung Medical Center. We assessed the objective response rate (ORR), progression-free survival (PFS), time to next treatment (TTNT), and overall survival (OS) between treatment groups. Subgroup analyses were conducted in the CT + IO group according to the type of AGAs and PD-L1 expression.

RESULTS: In total, 163 NSCLC patients with AGAs other than common EGFR, ALK, and ROS1 were included, with a median age of 62.4 years. 57 (35.0%) patients received CT + IO and 106 (65.0%) received CT. The proportions of patients with EGFR exon 20 insertion (E20I), HER2 mutation (mHER2), RET fusion (RET), and MET exon 14 skipping (METex14) were 28.8% (n = 47), 39.9% (n = 65), 16.6% (n = 27), and 14.7% (n = 24), respectively. With 32.0 months of median follow-up duration (range: 28.5-37.0), median PFS was 8.0 months (95% CI, 6.0-12.8) in CT + IO and 6.4 months (95% CI, 5.5-8.0) in CT (HR: 0.71, 95% CI, 0.49-1.03). In CT + IO group, median PFS by AGAs were 5.0 months (95% CI, 3.2-NA), 8.3 months (95% CI, 6.0-NA), 5.8 months (95% CI, 4.5-NA), and 17.1 months (95% CI, 10.7-NA) for E20I, mHER2, RET and METex14 respectively. Among these, 44.4% of METex14 patients had a PD-L1 TPS of 50% or higher. 24-month OS rate according to PD-L1 expression were 45.4%, 56.3%, and 81.5% in PD-L1 TPS < 1%, 1 to 49%, and ≥ 50%.

CONCLUSIONS: The combination of chemotherapy with ICIs in NSCLC patients with AGAs other than common EGFR, ALK, and ROS1 mutations demonstrated similar clinical outcomes compared to conventional chemotherapy. Patients with METex14 were associated with higher response rate and longer PFS among patients with AGAs when treated with chemotherapy plus ICIs. Also, the efficacy of the chemotherapy plus ICIs is positively correlate to the PD-L1 expression.

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BACKGROUND: Anesthetic exposure in young children raises concerns about neurodevelopmental safety, with preclinical evidence suggesting potential neurotoxicity of volatile anesthetics. This study aimed to assess whether the combination of dexmedetomidine and remifentanil, by reducing sevoflurane exposure, has any differential effect on neurodevelopmental outcomes in young children compared with sevoflurane alone.

METHODS: This study was a prospective, double-blind, randomized clinical trial including children younger than 2 yr undergoing nonstaged, nonrepetitive surgeries. Participants received dexmedetomidine and remifentanil as adjuncts to sevoflurane (DEX-R group) or sevoflurane alone (control group). The study assessed their neurodevelopmental status at 28 to 30 months using the Korean Leiter International Performance Scale and the Child Behavior Checklist, as predefined secondary outcomes. The primary endpoint-full-scale IQ at 5 yr of age-will be reported after completion of long-term follow-up.

RESULTS: Among 400 enrolled participants, 343 completed assessments (169 control, 176 DEX-R). There was no difference in the mean anesthesia duration between the control and DEX-R groups (77.1 min vs. 72.8 min; mean difference [95% CI], 4.4 [-3.8 to 12.6]; P = 0.293). The mean end-tidal sevoflurane concentration was significantly lower in the DEX-R group than in the control group (1.8 vol% vs. 2.6 vol%; mean difference [95% CI], -0.9 [-1.0 to -0.7] vol%; P < 0.001). The mean full-scale IQ score was 102.5 ± 11.5 in the DEX-R group and 103.6 ± 11.5 in the control group (mean difference, -1.1; 95% CI, -3.9 to 1.7; P = 0.442). No significant difference was observed in the Child Behavior Checklist total score between groups.

CONCLUSIONS: The addition of dexmedetomidine and remifentanil to sevoflurane anesthesia was not associated with significant differences in neurodevelopmental outcomes at 28 to 30 months compared to sevoflurane alone.

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BACKGROUND: This study aimed to evaluate the relationship between surrogate efficacy outcomes and overall survival (OS) in clinical trials for recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC), and to develop a predictive model for OS that incorporates these surrogate outcomes while accounting for baseline patient characteristics.

MATERIALS AND METHODS: Data were systematically collected from first-line trials published between January 2010 and March 2025 for R/M HNSCC. Five machine learning models were assessed to predict OS based on surrogate outcomes [objective response rate (ORR), disease control rate, progression free survival (PFS), duration of response, 1-year OS rate] and patient characteristics [human papillomavirus (HPV) status, Eastern Cooperative Oncology Group (ECOG) performance status, programmed death-ligand 1 (PD-L1) expression]. Retrospective data from a single institution was utilized to create simulated datasets for additional validation.

RESULTS: Analysis included 90 treatment arms [26 immune checkpoint inhibitor (ICI)-based and 64 non-ICI], extracted from 52 publications. The strongest correlation with median OS was the 1-year OS rate (r = 0.87, P < 0.001). ORR and median PFS showed positive correlations with OS overall, but these correlations were not significant within the ICI subgroup. The Elastic Net model demonstrated strong performance on the held-out test set (r = 0.74, P < 0.001) and the simulated validation set (r = 0.75, P < 0.001). Model interpretation showed that 1-year OS rate and ORR had the strongest impact on predicted OS among surrogate outcomes. Among patient characteristics, the proportion of ECOG 0 and HPV positivity impacted predicted OS across all regimens, while PD-L1 positivity impacted OS only in ICI-based regimens.

CONCLUSION: The Elastic Net model effectively bridges surrogate efficacy endpoints and median OS, facilitating the interpretation of early clinical trial outcomes and assisting in the prediction of OS benefit in R/M HNSCC.

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Ecklonia stolonifera is an edible marine seaweed that contains a high amount of phlorotannins, including phlorofucofuroeckol A (PFFA) and dieckol that have a range of pharmacologic effects. Here we report that these two phlorotannins block the interactions between the deubiquitinase USP5 and the Cav3.2 T-type calcium channel which we previously identified as a unique molecular target for pain. PFFA and dieckol delivered intrathecally (10 μg/i.t.) or intragastrically (30 mg/kg, p.o.) inhibited both phases of formalin-induced nocifensive behaviors and eliminated thermal hyperalgesia in a chronic inflammatory pain model induced by administering complete Freund's adjuvant (CFA) to the hind paws of male and female mice. Dieckol but not PFFA lost its analgesic effects in Cav3.2 null mice treated with CFA, suggesting that Cav3.2 channels are not essential for the in vivo actions of PFFA, but are required for those exerted by dieckol. Overall, our results suggest that phlorotannins derived from edible marine seaweeds, particularly PFFA, could be a novel class of analgesics that target the Cav3.2/USP5 interaction.

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INTRODUCTION: Uncommon EGFR mutations comprise 10% to 20% of all EGFR mutations in NSCLC and generally report reduced responsiveness to EGFR tyrosine kinase inhibitors (TKIs). Lazertinib, a third-generation EGFR-TKI, has found efficacy in common EGFR mutations, but its potential in uncommon mutations remains unexplored. This study investigated the efficacy and safety of lazertinib in patients with NSCLC with uncommon EGFR mutations.

METHOD: This single-arm, multicenter phase II trial enrolled patients with advanced NSCLC harboring uncommon EGFR mutations excluding exon 20 insertions. Patients received lazertinib 240 mg daily until disease progression or unacceptable toxicity. The primary end point was objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end points included progression-free survival (PFS), overall survival (OS), duration of response (DoR), and safety.

RESULTS: Among 36 patients enrolled, the ORR was 50.0% (95% confidence interval [CI]: 34.5%-65.5%), with 18 partial responses, meeting the primary end point. Disease control rate was 88.9% (95% CI: 74.1%-96.2%). Patients with major uncommon mutations (G719X, L861Q, S768I) reported an ORR of 54.8% (17/31). Median PFS was 10.8 months (95% CI: 4.4-19.2), and median DoR was 15.1 months. G719X mutations reported the highest response (ORR 61%, median PFS 20.3 months), followed by S768I (ORR 60%) and L861Q (ORR 58%, median PFS 9.5 months). Treatment-emergent adverse events occurred in all patients, with grade 3 or higher events in 33.3%; most common were rash (47.2%), pruritus (36.1%), and muscle spasms (33.3%).

CONCLUSIONS: Lazertinib reported promising efficacy and a manageable safety profile in patients with NSCLC with uncommon EGFR mutations, particularly for G719X, S768I, and L861Q subtypes. These results suggest lazertinib could be an effective treatment option for this heterogeneous patient population with limited therapeutic alternatives.

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BACKGROUND: There has been little investigation of predictive biomarkers and resistance mechanisms of amivantamab, an EGFR, and MET targeting bispecific antibody in EGFR ex20ins. Here, we investigated the correlation of molecular profile with clinical outcome using cell-free NGS (cf-NGS) in patients treated with amivantamab.

METHODS: Plasma samples from PCR or NGS-confirmed EGFR ex20ins patients (n = 30) treated with amivantamab were prospectively and longitudinally collected for analysis. The Guardant OMNI research-use-only assay was used for molecular profiling.

RESULTS: cfNGS analysis was performed on 62 samples from 25 patients. Baseline cfDNA-based NGS results demonstrated that patients with an EGFR ex20ins variant allele frequency (VAF) < 1 % (n = 11) showed higher objective response rate (45.4 vs 35.7 %), durable clinical benefit ratio (81.8 vs 21.4 %), and longer progression-free survival (PFS) (16.5 vs 2.6 months, hazard ratio [HR] 0.40, p < 0.01) compared to those with VAF ≥ 1 % (n = 14). The most common concurrent alteration was TP53 (n = 14, 56.0 %) which showed no correlation with clinical outcome while concomitant EGFR amplification (n = 9, 36.0 %) showed significantly shorter PFS (11.1 vs 2.7 months, HR 0.35, p < 0.05). Paired analysis showed a significant difference in PFS based on the dynamics of EGFR ex20ins VAF compared to the baseline and during treatment. Additionally, we identified several acquired resistance mechanisms to amivantamab.

CONCLUSIONS: Our findings underscore the significant predictive value of baseline EGFR ex20ins VAF for amivantamab treatment. Furthermore, changes in ctDNA VAF during treatment emphasize the role of early ctDNA dynamics as critical predictors of therapeutic response and long-term outcomes, which may inform treatment strategies.

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This study investigated the effects of feature augmentation, which uses generated images with specific imaging features, on the performance of isocitrate dehydrogenase (IDH) mutation prediction models in gliomas. A total of 598 patients were included from our institution (310 training, 152 internal test) and the Cancer Genome Atlas (136 external test). Score-based diffusion models were used to generate T2-weighted, FLAIR, and contrast-enhanced T1-weighted image triplets. Three neuroradiologists independently assessed visual Turing tests and various morphological features. Multivariable logistic regression models were developed using real images, random augmented data, and feature-augmented datasets. While random augmentation yielded models with AUCs comparable to real image-based models, it led to reduced specificity, particularly in the external test set (specificity: 83.2% vs. 73.0%, P = .013). In contrast, feature-augmented models maintained stable diagnostic performance; however, when more than 70% of training images included synthetic T2-FLAIR mismatch signs, AUC decreased in the external test set (AUC: 0.905-0.906 for ≤ 70%; 0.902-0.876 for ≥ 80%). These findings highlight the value of phenotype-specific augmentation for IDH prediction, while emphasizing the need to optimize augmentation proportion to avoid performance degradation.

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PURPOSE: The surveillance protocol for early-stage non-small cell lung cancer (NSCLC) is not contingent upon individualized risk factors for recurrence. This study aimed to use comprehensive data from clinical practice to develop a deep-learning model for practical longitudinal monitoring.

METHODS: A multimodal deep-learning model with transformers was developed for real-time recurrence prediction using baseline clinical, pathological, and molecular data with longitudinal laboratory and radiologic data collected during surveillance. Patients with NSCLC (stage I to III) who underwent surgery with curative intent between January 2008 and September 2022 were included. The primary outcome was predicting recurrence within 1 year after the monitoring point. This study demonstrates the timely provision of risk scores (RADAR score) and determined thresholds and the corresponding AUC.

RESULTS: A total of 14,177 patients were enrolled (10,262 with stage I, 2,380 with stage II, and 1,703 with stage III). The model incorporated 64 clinical-pathological-molecular factors at baseline, along with longitudinal laboratory and computed tomography imaging interpretation data. The mean baseline RADAR score was 0.324 (standard deviation [SD], 0.256) in stage I, 0.660 (SD, 0.210) in stage II, and 0.824 (SD, 0.140) in stage III. The AUC for predicting relapse within 1 year of the monitoring point was 0.854 across all stages, with a sensitivity of 86.0% and a specificity of 71.3% (AUC = 0.872 in stage I, AUC = 0.737 in stage II, and AUC = 0.724 in stage III).

CONCLUSION: This pilot study introduces a deep-learning model that uses multimodal data from routine clinical practice to predict relapses in early-stage NSCLC. It demonstrates the timely provision of RADAR risk scores to clinicians for recurrence prediction, potentially guiding risk-adapted surveillance strategies and aggressive adjuvant systemic treatment.

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BACKGROUND: This study aimed to evaluate the efficacy and safety of adjuvant pembrolizumab in patients with completely resected stage I lung adenocarcinoma with micropapillary or solid-pattern (MPSOL).

METHODS: This was a single-center, single-arm phase 2 study (ClinicalTrials.gov identifier: NCT03254004). Key eligibility criteria included patients with stage I lung adenocarcinoma (per the American Joint Committee on Cancer 8th edition; primary tumor of <4 cm and without nodal metastasis), characterized by MPSOL histological subtype upon postsurgical pathological examination Patients were treated with pembrolizumab 200 mg every 3 weeks for 1 year or until disease recurrence or intolerable toxicity. The primary endpoint was 3-year disease-free survival (DFS), defined as the time from surgery to recurrence or death from any cause. Secondary endpoints included overall survival and safety.

FINDINGS: Between September 17, 2018, and February 10, 2022, 70 patients were enrolled. At a median follow-up of 45·0 months, the 3-year disease-free survival (DFS) was 83·2%, meeting the survival endpoint of >80%. Patients with EGFR mutations showed significantly poorer DFS than those with EGFR wild-type (hazard ratio [HR]: 5·01 [95% confidence interval (CI): 1·11-22·70], P = 0·036), although no significant differences were noted according to age, smoking status, tumor size, and PD-L1 tumor proportion score. Grade 3 or 4 treatment-related adverse events (AEs) occurred in 6 patients (8·6%). Thirteen AEs led to treatment discontinuation and the majority of these AEs resolved upon discontinuation and subsequent steroid treatment.

INTERPRETATION: Adjuvant pembrolizumab exhibited promising clinical efficacy in patients with stage I lung MPSOL, particularly those with EGFR-wild type, and exhibited tolerable safety.

FUNDING: Merk Sharp & Dohme (MSD). The funders had no role in study design, data collection, data analysis, interpretation, or writing of the report.

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Dacomitinib demonstrated superior survival benefit compared to gefitinib as a first-line treatment in non-small cell lung cancer (NSCLC) patients with common EGFR mutations through ARCHER 1050. However, there is limited real-world data concerning its efficacy and safety. This study included patients with EGFR-mutant NSCLC who received dacomitinib as a first-line treatment between January 2021 and December 2022 at Samsung Medical Center and St. Vincent's Hospital. This study assessed the objective response rate (ORR), progression-free survival (PFS), overall survival (OS), safety profile of dacomitinib, and subsequent treatments after dacomitinib failure. In total, 153 patients were included in this study. Exon 19 deletion was observed in 50.3% of patients, while the L858R mutation in exon 21 was observed in 46.4% of patients. 45.1% of patients had brain metastasis. The ORR was 84.3%. The median follow-up duration was 16.9 months, with a median PFS of 16.7 months (95% CI, 14.4 to 25.2). Based on the type of EGFR mutation, the median PFS was 18.1 months (95% CI, 14.5 to NE) in patients with exon 19 deletion, and 15.9 months (95% CI, 12.5 to NE) in patients with L858R mutation. Grade 3 or higher adverse events were observed in 7.2% of patients. Initially administered at a dose of 45 mg, dose reduction was necessary for 85.6% of patients, with a final dosage of 30 mg in 49.0% and 15 mg in 36.6% of cases. Out of the 60 patients who experienced disease progression, 31 underwent tissue re-biopsy and 25 underwent liquid biopsy. Overall, T790M mutation was detected in 40.9% of patients who progressed after dacomitinib. The survival benefit of dacomitinib has been demonstrated, indicating its promising efficacy in a real-world setting. The detection rate of the T790M mutation after dacomitinib treatment failure was comparable to that of other second-generation EGFR-TKIs.

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As a part of our ongoing search for bioactive constituents of Artemisia capillaris, we isolated 4-O-caffeoyl-2-C-methyl-d-threonic acid (PPT-14). This is a rare caffeic acid ester derivative that is reported here for the first time in the Artemisia species, which is the third occurrence in any plant species worldwide. In this study, we evaluated the anti-diabetic potential of PPT-14 using in vitro and in silico approaches. PPT-14 demonstrated significant inhibitory activity against two crucial enzymes linked to diabetes progression and complications: protein tyrosine phosphatase 1B (PTP1B) and aldose reductase (AR). These had IC50 values of 64.92 and 19.50 µM, respectively. Additionally, PPT-14 exhibited free radical scavenging activity with 2,2-diphenyl-2-picrylhydrazyl (IC50 14.46 µM). Molecular docking and 200 ns molecular dynamics simulations confirmed that there were stable binding interactions with the key residues of PTP1B and AR, highlighting strong affinity and dynamic stability. Pharmacokinetic analyses revealed favorable water solubility, adherence to Lipinski's Rule of Five, and minimal interactions with cytochrome P450 enzymes, indicating the drug-like potential of PPT-14. Toxicity studies confirmed its safety profile, showing no genotoxicity, hepatotoxicity, or significant toxicity risks, with an acceptable oral LD50 value of 2.984 mol/kg. These findings suggest that PPT-14 could be a promising multitarget lead compound for ameliorating diabetes and its associated complications.

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INTRODUCTION: Although osimertinib, a third-generation EGFR tyrosine kinase inhibitor, as the first-line therapy for metastatic NSCLC was found to have substantial survival benefits, concerns have arisen regarding its potential cardiotoxicity, particularly in real-world clinical settings. We aimed to investigate the incidence, risk factors, and reversibility of osimertinib-related cardiotoxicity.

METHODS: We analyzed 1126 patients with NSCLC treated with osimertinib from May 2016 to April 2023 in two cancer centers. Osimertinib-related cardiotoxicity was defined as a composite of osimertinib-related cardiac dysfunction (ORCD), newly developed arrhythmia, and cardiac death. Total follow-up duration was 20.6 (10.8-35.2) months.

RESULTS: The osimertinib was administered for a median of 12.4 months. The incidence of osimertinib-related cardiotoxicity was 4.7%. Advanced age (adjusted hazard ratio with 95% confidence interval: 1.07 [1.04-1.09], p < 0.001), a history of heart failure (3.35 [1.67-9.64], p = 0.025), atrial fibrillation (3.42 [1.27-9.22], p = 0.015), and baseline low left ventricle strain (0.87 [0.79-0.96], p = 0.005) were independently associated with development of cardiotoxicity. The recovery rate of ORCD was 82.4%, which did not differ between patients who discontinued medication and those who did not.

CONCLUSIONS: In real-world practice, the incidence of osimertinib-related cardiotoxicity was 4.7%, including 3.4% for ORCD requiring cardiologic intervention, which is higher than previously reported. Given the long-term medication of osimertinib and increased mortality associated with cardiotoxicity, vigilant monitoring is crucial, especially in patients with advanced age, history of heart failure, atrial fibrillation, or decreased baseline left ventricular strain.

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Research on perovskite light-emitting diodes (PeLEDs) has primarily focused on modulating crystal growth to achieve smaller grain sizes and defect passivation using organic additives. However, challenges remain in controlling the intermolecular interactions between these organic additives and perovskite precursor ions for precise modulation of crystal growth. In this study, we synthesize two triphenylphosphine oxide (TPPO)-based multidentate additives: bidentate hexane-1,6-diyl-bis(oxy-4-triphenylphosphine oxide) (2-TPPO) and tetradentate pentaerythrityl-tetrakis(oxy-4-triphenylphosphine oxide) (4-TPPO). We investigate the crystallization of perovskites through real-time crystal growth analyses and theoretical calculations. As the extent of multidentate binding increases, perovskite crystallization slows down gradually. The multidentate TPPO additives exhibit strong binding to Pb2+ ions through multidentate ligation in the precursor solution, leading to retarded halide-mediated crystal growth, reduced crystallite size, and enhanced exciton binding energy. Moreover, these multidentate additives reduce trap-mediated nonradiative losses by forming stronger multiple bonds with undercoordinated Pb2+ defects in perovskite films, while also promoting effective strain relaxation. The synergistic effects of the multifunctional and multidentate 4-TPPO additive result in highly efficient PeLEDs, with a maximum current efficiency of 81.12 cd A-1 and a maximum external quantum efficiency of 25.19%. Our findings demonstrate the successful manipulation of crystallization dynamics through the control of additive and Pb2+ multidentate binding interactions, presenting an effective strategy for application-specific crystal growth.

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INTRODUCTION: The addition of programmed cell death protein-1 (PD-1) inhibitors to chemotherapy (CT) or anti-CTLA4 (ipilimumab) has recently emerged as an effective first-line (1L) treatment for esophageal squamous cell carcinoma (ESCC), the most common form of esophageal cancer globally.

METHODS: A systematic literature review (SLR) was conducted to identify randomized controlled trials (RCTs) investigating 1L PD-1 inhibitor regimens in adult patients with unresectable, locally advanced, or metastatic ESCC. Bayesian NMAs were conducted to evaluate overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and grade ≥3 treatment-related adverse events (TRAEs).

RESULTS: Three eligible RCTs were identified, evaluating three PD-1 inhibitor regimens with broad regulatory approval for 1L ESCC in combination with CT (tislelizumab, nivolumab, and pembrolizumab). Tislelizumab + CT demonstrated similar long-term OS to nivolumab + CT and pembrolizumab + CT but a significant PFS benefit over nivolumab + CT and comparable efficacy to pembrolizumab + CT. Subgroup analyses were consistent with the base case, including among patients with varying PD-L1 expression (≥1% and ≥5% Tumor Area Positivity [TAP] score or ≥1 and ≥5 combined positive score [CPS]), Asia versus the rest of world, and different underlying CT backbones. Safety profiles were comparable across the three treatments.

CONCLUSION: Tislelizumab + CT is an effective 1L treatment option for advanced or metastatic ESCC, demonstrating comparable efficacy and safety outcomes relative to existing treatments.

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INTRODUCTION: Atopic dermatitis (AD) is often associated with gastrointestinal symptoms, including anorexia and alterations in the gut microbiome. A traditional East Asian herbal medicine Bojungikgi-tang (BJT; Buzhongyiqi-tang in Chinese, Hochuekki-To in Japanese) has been commonly used to manage AD and anorexia. This study aimed to evaluate the effects and safety of BJT in anorexic patients with AD and to investigate its therapeutic mechanism through gut microbiome analysis.

METHODS: The trial included 26 adults with AD and anorexia, randomized (1:1) into BJT or waiting list groups for 12 weeks, including 8 weeks of treatment and 4 weeks of follow-up. The severity of anorexia and AD was assessed using the Visual Analog Scale (VAS), SCORing of Atopic Dermatitis (SCORAD), and Dermatology Life Quality Index (DLQI). Serum cytokine concentrations were measured before and after treatment using a multiplex immunoassay. Fecal samples were collected before and after treatment, and 16S rRNA sequencing was performed to analyze the gut microbiota.

RESULTS: The BJT group showed a significant decrease in anorexia VAS scores compared to the waiting list group at 8 weeks. Only the BJT group showed significant improvements in SCORAD and DLQI scores compared to baseline, with effects maintained through follow-up. No serious adverse events related to BJT were reported. Among the serum cytokines, IL-1β significantly decreased only in the BJT group, while IL-4 and IL-17 significantly decreased in both groups, with a more pronounced reduction observed in the BJT group. After 8 weeks of BJT treatment, significant changes were observed in the gut microbiome, including alterations in the Gemella genus, Gemmiger formicilis, and Blautia_uc species.

CONCLUSION: BJT may improve symptoms of anorexia and AD without serious adverse events, potentially through modifications in the gut microbiota.

CLINICAL TRIAL REGISTRATION: The study protocol was registered at the Clinical Research Information Service (KCT0006784, https://cris.nih.go.kr/cris/search/detailSearch.do?seq=21298&search_page=L).

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INTRODUCTION: This study aimed to report the efficacy and safety of adjuvant sequential chemotherapy after definitive treatment of salivary duct carcinoma (SDC) compared with the standard treatment alone (surgery with postoperative radiation therapy).

METHODS: This was a retrospective study of pathologically confirmed 135 SDC patients (study period 2009 to 2022). After curative surgery and adjuvant radiation therapy, 55 of 135 patients decided to receive additional chemotherapy (OP + RT + chemo group), while 80 opted for surgery and radiation (OP + RT group). Treatment outcomes of overall survival (OS), disease-free survival (DFS), and distant metastasis-free survival (DMFS) were compared using a propensity score matching (PSM) analysis.

RESULTS: Adjuvant chemotherapy consisted of three cycles of cisplatin-based regimen, which was well tolerated in most patients with minimal adverse events. Multivariable analyses indicated that the addition of chemotherapy did not improve OS (p = 0.05), DFS (p = 0.386), and DMFS (p = 0.735), although there was a trend toward favoring adjuvant chemotherapy in terms of OS. With PSM analysis, OS (OP + RT + chemo to OP + RT, hazard ratio [HR] = 0.40, 95% confidence interval [95% CI] = 0.12-1.29, p = 0.126), DFS (HR = 0.69, 95% CI = 0.30-1.56, p = 0.367), and DMFS (HR = 0.96, 95% CI = 0.46-1.99, p = 0.903) were not statistically different.

CONCLUSIONS: Current cisplatin-based adjuvant chemotherapy did not significantly improve treatment outcomes of SDC patients over the surgery and adjuvant radiation. Further development or clinical studies are required to improve the outcomes of SDC, including chemotherapeutic, biomarkers, immune checkpoint inhibitors, or treatment strategies.

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BACKGROUND: The need for research on individual home therapies to promote continued community-dwelling among older adults with mild dementia is growing. This study aimed to compare the effects of individual occupation-based reminiscence therapy at home (IOBRT-H) and individual occupation-based reminiscence therapy in a dementia care centre (IOBRT-DCC) on cognitive function, depression, and instrumental activities of daily living (IADL) among community-dwelling older adults with mild dementia.

METHODS: This study was a randomised controlled trial. Twenty-six community-dwelling older adults with mild dementia were randomised to the IOBRT-H (n = 13) and IOBRT-DCC (n = 13) groups. The intervention was conducted for 10 weeks, with one session a week and each session lasting 60 min for both groups. Cognitive function was assessed using the Allen Cognitive Level Screen (ACLS), depression with the short form of the Geriatric Depression Scale Korean version (SGDS-K), and IADL using the Seoul-Instrumental Activities of Daily Living (S-IADL).

RESULTS: Both the IOBRT-H and IOBRT-DCC groups showed significant improvements in ACLS scores (P < 0.01 and P < 0.01, respectively). The SGDS-K score decreased only in the IOBRT-H group (P < 0.01). Between the groups, the IOBRT-H group had significantly greater improvements in both ACLS and SGDS-K scores than the IOBRT-DCC group (P < 0.05 and P < 0.05, respectively).

CONCLUSION: This study's results indicated the potential for applying IBORT-H as an intervention to improve cognitive function and reduce depression in community-dwelling older adults with mild dementia. We expect the findings of this study to serve as useful foundational data for developing home-visiting cognitive programs.

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INTRODUCTION: The role of maintenance durvalumab after definitive concurrent chemoradiotherapy (CCRT) in unresectable locally advanced NSCLC with EGFR mutation or ALK translocation remains unclear. We compared the effectiveness of durvalumab maintenance therapy in groups with EGFR and ALK wild-type versus those with EGFR or ALK mutations.

METHODS: In this retrospective multicenter observational study, patients with locally advanced NSCLC without progression after CCRT followed by maintenance durvalumab and available molecular test results (EGFR and ALK) were eligible. The primary objective was to compare progression-free survival (PFS) between EGFR and ALK wild-type and EGFR or ALK mutant NSCLC. Secondary objectives include overall survival according to EGFR or ALK mutation and programmed death-ligand 1 (PD-L1) expression.

RESULTS: Among 339 patients, 279 had wild-type EGFR/ALK, 41 had EGFR mutations and 19 had ALK translocations. The median age was 68 years with 276 male individuals (81.4%) and 63 female individuals (18.6%), 165 (49.3%) had adenocarcinoma, 149 (44.5%) had squamous cell carcinoma, and 21 (6.3%) had other histologic types, 120 (35.4%) had stage IIIA, 168 (49.6%) stage IIIB, and 51 (15.0%) had stage IIIC. Most of the patients (n = 288, 85%) achieved partial response to CCRT, two (0.6%) had a complete response, and 49 patients (14.4%) had stable disease. Excluding four patients with unknown PD-L1 tumor proportion score (TPS), 16 (4.8%) had a PD-L1 TPS of 0, 168 (50.1%) had 1 to 49, and 151 (45.1%) had 50 or higher. The median PFS was 21.4 months (95% confidence interval [CI]: 17.3-25.3) for the EGFR/ALK wild-type group and 21.0 months (95% CI: 15.7-not available [NA]) for the EGFR or ALK mutant group with no difference (p = 0.74). Significant differences occurred in PFS on the basis of PD-L1 expression with values of 13.6 (95% CI: 10.5-NA), 18.7 (95% CI: 15.1-26.9), and 24.7 (95% CI: 20.7-NA) months for TPS of 0, 1-49, and 50 or higher, respectively (p = 0.02).

CONCLUSIONS: Durvalumab maintenance therapy after definitive CCRT in unresectable locally advanced NSCLC patients with EGFR or ALK mutation demonstrates comparable clinical outcomes to those with wild-type EGFR/ALK when PD-L1 expression is present.

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Introduction: Dry eye disease (DED) is a very frequently encountered ocular disease, making it a growing public health burden. However, current treatments for DED present unmet medical needs owing to their side effects or ineffectiveness. Therefore, an effective and safe therapeutic agent to manage DED is needed. Method and Analysis: We planned a phase 2, dose-finding, double-blind, randomized placebo-controlled trial to evaluate the efficacy and safety of two different doses of USL (Useul), the extract of Achyranthis Radix, compared with placebo, for DED. USL has been found to protect against DED by inducing tear secretion and improving corneal irregularity via anti-inflammatory effects, which will provide new therapeutic options. One hundred and twenty participants will be enrolled, after assessing the inclusion/exclusion criteria, at Daejeon University Daejeon Korean Medicine Hospital. Enrolled participants will be allocated to standard-dose USL, high-dose USL, or placebo groups in a 1:1:1 ratio and will be required to administer the trial medication twice a day for 12 weeks and visit the clinic five times. For efficacy outcomes, objective endpoints of fluorescein corneal staining score, tear break-up time, Schirmer's test, and meibomian test and subjective endpoints of Ocular Surface Disease Index, visual analog scale, Standard Patient Evaluation for Eye Dryness-II, and biomarkers will be assessed throughout the trial. Safety will be assessed based on adverse events, vital signs, laboratory tests, visual acuity, and intraocular pressure. Discussion: Our study results are expected to provide clinical evidence for the use of DED as an effective and safe agent for DED.

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This study investigates the variability among patients with non-small cell lung cancer (NSCLC) in their responses to immune checkpoint inhibitors (ICIs). Recognizing that patients with advanced-stage NSCLC rarely qualify for surgical interventions, it becomes crucial to identify biomarkers that influence responses to ICI therapy. We conducted an analysis of single-cell transcriptomes from 33 lung cancer biopsy samples, with a particular focus on 14 core samples taken before the initiation of palliative ICI treatment. Our objective was to link tumor and immune cell profiles with patient responses to ICI. We discovered that ICI non-responders exhibited a higher presence of CD4+ regulatory T cells, resident memory T cells, and TH17 cells. This contrasts with the diverse activated CD8+ T cells found in responders. Furthermore, tumor cells in non-responders frequently showed heightened transcriptional activity in the NF-kB and STAT3 pathways, suggesting a potential inherent resistance to ICI therapy. Through the integration of immune cell profiles and tumor molecular signatures, we achieved an discriminative power (area under the curve [AUC]) exceeding 95% in identifying patient responses to ICI treatment. These results underscore the crucial importance of the interplay between tumor and immune microenvironment, including within metastatic sites, in affecting the effectiveness of ICIs in NSCLC.

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Acanthopanax senticosus belongs to Araliaceae family and is traditionally used as a tonic. The roots and stems are mainly used as treatments for hypodynamia, rheumatism, and hypertension, but their frequent use may lead to extinction. However, comprehensive and simultaneous analysis of the remaining parts were still limited. There is a need to reorganize them for standardization of functional foods. In this study, 50 phenolic compounds and 82 triterpenoid saponins from the shoots, leaves, fruits, and stems of were characterized using UPLC-QTOF-MS and UPLC-QTRAP-MS/MS. Among them, 52 compounds were newly determined as the cis and malonyl-bound phenolic acids and were found to be structural isomers of Acanthopanax flavonoids and saponins. All compounds were absolutely/relatively quantified, and shoots had the highest content. Peroxynitrite and α-glucosidase inhibitory activities were performed, followed by evaluation of structure-activity relationships. Particularly, hederasaponin B and ciwujianoside B showed remarkable efficacy, which were affected by the C-23 hydroxylation, the C-20(29) double bond, and the presence of rhamnose. These detailed profiling can be used as fundamental data for increasing the utilization of A. senticosus and developing them into functional foods.

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Generative artificial intelligence (AI) has been applied to images for image quality enhancement, domain transfer, and augmentation of training data for AI modeling in various medical fields. Image-generative AI can produce large amounts of unannotated imaging data, which facilitates multiple downstream deep-learning tasks. However, their evaluation methods and clinical utility have not been thoroughly reviewed. This article summarizes commonly used generative adversarial networks and diffusion models. In addition, it summarizes their utility in clinical tasks in the field of radiology, such as direct image utilization, lesion detection, segmentation, and diagnosis. This article aims to guide readers regarding radiology practice and research using image-generative AI by 1) reviewing basic theories of image-generative AI, 2) discussing the methods used to evaluate the generated images, 3) outlining the clinical and research utility of generated images, and 4) discussing the issue of hallucinations.

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BACKGROUND: The tumor immune microenvironment in cancer treatment response and resistance is of increasing interest. This retrospective study characterized and investigated programmed death-ligand 1 (PD-L1), PD-L2, and the immune gene expression signature and their association with clinical outcomes in locoregionally advanced head and neck squamous cell carcinoma (LA HNSCC).

PATIENTS AND METHODS: PD-L1 and PD-L2 expression on tumor and immune-infiltrating cells (positivity defined as combined positive score or immunohistochemistry proportion score >1) and T-cell-inflamed gene expression profile (TcellinfGEP) were evaluated in patients with LA HNSCC treated in South Korea from 2000 to 2015. Correlations among the three biomarkers and their associations with overall survival and recurrence-free survival were assessed.

RESULTS: Among 366 patients, 38.8% had human papillomavirus-positive disease. PD-L1-positive, PD-L2-positive, and high TcellinfGEP (≤-0.162) status were observed in 83.6%, 85.4%, and 73.2% of patients, respectively; 4.1% were posttreatment samples. Correlation between PD-L1 and PD-L2 scores was moderate (rSpearman = 0.50), and each biomarker was slightly less correlated with TcellinfGEP (0.41-0.45). PD-L1 expression and high TcellinfGEP status were associated with human papillomavirus positivity. Higher levels of all biomarkers were observed in oral cavity and oropharyngeal cancers compared with other HNSCC sites. In a multivariable analysis that simultaneously adjusted for all three biomarkers, only high TcellinfGEP was significantly associated with longer overall survival (adjusted hazard ratio, 0.57; 95% confidence interval 0.33-0.98) and recurrence-free survival (adjusted hazard ratio, 0.41; 95% confidence interval 0.23-0.74).

CONCLUSION: High TcellinfGEP status, but not PD-L1 or PD-L2 expression, was independently associated with longer survival in patients with LA HNSCC. Results may have implications for evaluating therapies targeting programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) in HNSCC.

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BACKGROUND: Neoadjuvant chemoradiotherapy (nCRT) followed by radical esophagectomy is the standard treatment for locally advanced esophageal squamous cell cancer (LA-ESCC). However, various nCRT regimens have been used, and their comparative efficacy and safety remain unclear.

METHODS: Patients with histologically confirmed LA-ESCC who underwent nCRT followed by radical esophagectomy between January 2016 and February 2022 were enrolled in this study. Of note, 3 different nCRT regimens were retrospectively compared: conventional radiotherapy (RT) + cisplatin/5-fluorouracil (FP) (Conv-FP), hypofractionated RT + FP (Hypo-FP), and regimens from the ChemoRadiotherapy for Oesophageal cancer followed by Surgery Study (CROSS) trial (CROSS). The overall survival (OS), pathologic complete response (pCR), toxicity, and treatment compliance rates were analyzed.

RESULTS: Among the 600 patients, 225 received Conv-FP, 255 received Hypo-FP, and 120 received the CROSS regimen. The OS rates at 1 year were 78.7%, 83.9%, and 88.1% in the Conv-FP, Hypo-FP, and CROSS groups, respectively (P < .001). The pCR rates were 30.6%, 33.9%, and 35.0%, respectively (P = .653). The overall incidence of grade 3 toxicities was 10.2%. Hematologic and nonhematologic toxicities of grade ≥ 3 were observed in 8.4% and 11.4%, 0% and 7.6%, and 5.5% and 0.8% in the Conv-FP, Hypo-FP, and CROSS groups, respectively (P = .002 and P = .030). Weight loss of > 5% was observed in 44.0%, 51.4%, and 32.5% in the Conv-FP, Hypo-FP, and CROSS groups, respectively (P < .001). In the multivariate analysis, clinical T stage (P = .004), N stage (P = .012), FP chemotherapy regimen (P = .013), surgical resection (P < .001), hematologic toxicity (P = .001), and weight loss (P = .004) were significantly associated with poor OS.

CONCLUSION: The choice of nCRT regimen did not significantly affect the pCR rates in patients with LA-ESCC. However, the CROSS regimen demonstrated better OS and lower toxicity, suggesting that it may be the optimal treatment option among the groups.

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Thyroid immune-related adverse events (irAEs) are associated with programmed cell death protein 1 (PD-1) blockade efficacy in non-small cell lung cancer (NSCLC). However, their independence from PD-L1 expression and quantitative impact on predicting PD-1 blockade efficacy remain unexplored. This multicenter, retrospective, longitudinal study from Korea included 71 metastatic NSCLC patients who underwent PD-L1 expression and thyroid function testing during PD-1 blockade. Disease progression by the Response Evaluation Criteria for Solid Tumors was the main outcome. Three-stage analyses were performed: (1) multivariate Cox regression models adjusted for PD-L1 expression according to thyroid irAEs; (2) subgroup analyses; (3) regrouping and comparing predictivity of current and alternative staging. Patients with thyroid irAE + exhibited a longer progression-free survival [7/20 vs. 34/51, adjusted HR 0.19 (0.07-0.47); P < 0.001] than those with thyroid irAE-, independent of PD-L1 expression; the results remained across most subgroups without interaction. The three groups showed different adjusted HR for disease progression (Group 1: PD L1 + and thyroid irAE + ; Group 2: PD-L1 + or thyroid irAE + : 5.08 [1.48-17.34]; Group 3: PD-L1- and thyroid irAE- : 30.49 [6.60-140.78]). Alternative staging (Group 1 in stage IVB → stage IVA; Group 3 in stage IVA → stage IVB) improved the prognostic value (PVE: 21.7% vs. 6.44%; C-index: 0.706 vs. 0.617) compared with the 8th Tumor-Node-Metastasis staging. Our study suggests thyroid irAEs and PD-L1 expression are independent biomarkers that improve predicting PD-1 blockade efficacy in NSCLC. Thyroid irAEs would be helpful to identify NSCLC patients who benefit from PD-1 blockade in early course of treatment.

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BACKGROUND: Next-generation sequencing (NGS) has become widely available but molecular profiling-guided therapy (MGT) had not been well established in the real world due to lack of available therapies and expertise to match treatment. Our study was designed to test the feasibility of a nationwide platform of NGS-guided MGT recommended by a central molecular tumor board (cMTB) for metastatic solid tumors.

PATIENTS AND METHODS: Patients with advanced or metastatic solid tumors with available NGS results and without standard treatment were enrolled. The cMTB interpreted the patients' NGS reports and recommended the following: (i) investigational medicinal products (IMPs) approved in other indications; (ii) alternative treatments; (iii) clinical trials. The primary variables were the proportion of patients with actionable genomic alterations and those receiving MGT as per cMTB recommendations. Others included treatment duration (TD), overall response rate (ORR), disease control rate (DCR), and safety.

RESULTS: From February 2021 to February 2022, 193 cases [99 (51.3%) men; median age 58 years (range 24-88 years); median line of previous treatment 3 (range 0-9)] from 29 sites were enrolled for 60 cMTB sessions. The median time from case submission to cMTB discussion was 7 days (range 2-20 days), and to IMP treatment initiation was 28 days (range 14-90 days). Actionable genetic alterations were found in 145 patients (75.1%). A total of 89 (46.1%) patients received actual dosing of IMPs, and 10 (5.2%) were enrolled in cMTB-recommended clinical trials, achieving an MGT rate of 51.3%. ORR and DCR of IMPs were 10.1% and 72.5%, respectively. The median TD was 3.5 months [95% confidence interval (CI) 2.8-5.5 months], and the 4-month TD rate was 44.9%. The median overall survival of patients who received IMPs was 6.9 months (95% CI 5.2-10.0 months).

CONCLUSION: KOSMOS confirmed the feasibility of MGT recommended by the cMTB, achieving a high MGT match rate and promising effectiveness in heavily pretreated advanced cancer patients.

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PURPOSE: Optimal treatment for stage IIIA/N2 non-small cell lung cancer (NSCLC) is controversial. We aimed to assess the efficacy and safety of adjuvant pembrolizumab for stage IIIA/N2 NSCLC completely resected after neoadjuvant concurrent chemoradiation therapy (CCRT).

MATERIALS AND METHODS: In this open-label, single-center, single-arm phase 2 trial, patients with stage IIIA/N2 NSCLC received adjuvant pembrolizumab for up to 2 years after complete resection following neoadjuvant CCRT. The primary endpoint was disease-free survival (DFS). Secondary endpoints included overall survival (OS) and safety. As an exploratory biomarker analysis, we evaluated the proliferative response of blood CD39+PD-1+CD8+ T cells using fold changes in the percentage of proliferating Ki-67+ cells from days 1 to 7 of cycle 1 (Ki-67D7/D1).

RESULTS: Between October 2017 and October 2018, 37 patients were enrolled. Twelve (32%) and three (8%) patients harbored EGFR and ALK alterations, respectively. Of 34 patients with programmed cell death ligand 1 assessment, 21 (62%), nine (26%), and four (12%) had a tumor proportion score of < 1%, 1%-50%, and ≥ 50%, respectively. The median follow-up was 71 months. The median DFS was 22.4 months in the overall population, with a 5-year DFS rate of 29%. The OS rate was 86% at 2 years and 76% at 5 years. Patients with tumor recurrence within 6 months had a significantly lower Ki-67D7/D1 among CD39+PD-1+CD8+ T cells than those without (p=0.036). No new safety signals were identified.

CONCLUSION: Adjuvant pembrolizumab may offer durable disease control in a subset of stage IIIA/N2 NSCLC patients after neoadjuvant CCRT and surgery.

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PURPOSE: BRAF mutations are detected in 30%-80% of papillary thyroid cancer (PTC) cases. DaBRAFenib and trametinib showed promising antitumor activity in patients with BRAFV600E-mutated metastatic melanoma and non-small cell lung cancer. This study aimed to evaluate the efficacy and safety of daBRAFenib and trametinib in patients with metastatic BRAFV600E-mutated thyroid cancer.

MATERIALS AND METHODS: This was a retrospective study to evaluate the efficacy of daBRAFenib and trametinib in patients with metastatic BRAFV600E-mutated PTC. The patients received daBRAFenib 150 mg twice daily and trametinib 2 mg once daily at the Samsung Medical Center. This study evaluated the progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR) overall survival (OS), and safety of daBRAFenib and trametinib.

RESULTS: Between December 2019 and January 2022, 27 PTC patients including eight patients with poorly differentiated or anaplastic transformation, received daBRAFenib and trametinib. The median age was 73.0 years, and the median follow-up period was 19.8 months. The majority (81.5%) had undergone thyroidectomy, while 8 patients had received prior systemic treatments. ORR was 73.1%, with 19 partial responses, and DCR was 92.3%. Median PFS was 21.7 months, and median OS was 21.7 months. Treatment-related adverse events included generalized weakness (29.6%), fever (25.9%), and gastrointestinal problems (22.2%). Dose reduction due to adverse events was required in 81.5% of the patients.

CONCLUSION: DaBRAFenib and trametinib demonstrated a high ORR with promising PFS; however, most patients with BRAFV600E-mutated metastatic PTC required a dose reduction.

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PURPOSE: Leptomeningeal metastases (LMs) exhibit a high incidence in patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) post-treatment with first- or second-generation EGFR tyrosine kinase inhibitors (TKIs). This investigation evaluates the efficacy, safety, and pharmacokinetics of 80 mg once daily osimertinib in patients with LMs resistant to prior first- or second-generation EGFR TKIs.

MATERIALS AND METHODS: In this phase II multicenter, open-label, single-arm study, 80 mg osimertinib was administered to patients with EGFR-mutated NSCLC who had developed LMs subsequent to treatment with prior EGFR TKIs. The primary end point was overall survival (OS), assessed alongside objective response rate by the blinded independent central review (BICR) and a pharmacokinetic analysis of plasma and cerebrospinal fluid (CSF) on the first day of cycles 3 and 6.

RESULTS: A total of 73 patients diagnosed with LM were treated with osimertinib, including 64 patients evaluable for the LM efficacy set-T790M negative (n = 62) and T790M positive (n = 2). The median OS in the full-analysis set was 15.6 months (95% CI, 11.5 to 20.2). The objective response rate for LM was 51.6%, including a 15.6% complete response, and the disease control rate was 81.3% by BICR in the LM efficacy evaluable set. The median LM progression-free survival by BICR was 11.2 months (95% CI, 7.7 to 15.3), the duration of response was 12.6 months (95% CI, 7.6 to 17.7), and OS was 15.0 months (95% CI, 11.3 to 18.7). Pharmacokinetic analysis showed that the CSF to free plasma osimertinib ratio was 22%. Most safety profiles were grade 1 and 2.

CONCLUSION: The study demonstrates significant intracranial efficacy and survival benefits of 80 mg once daily osimertinib in NSCLC patients with LMs. The data support considering daily 80 mg of osimertinib as a treatment option for EGFR-mutated NSCLC patients with LMs, irrespective of T790M mutation status.

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In recent years, next-generation sequencing (NGS)-based genetic testing has become crucial in cancer care. While its primary objective is to identify actionable genetic alterations to guide treatment decisions, its scope has broadened to encompass aiding in pathological diagnosis and exploring resistance mechanisms. With the ongoing expansion in NGS application and reliance, a compelling necessity arises for expert consensus on its application in solid cancers. To address this demand, the forthcoming recommendations not only provide pragmatic guidance for the clinical use of NGS but also systematically classify actionable genes based on specific cancer types. Additionally, these recommendations will incorporate expert perspectives on crucial biomarkers, ensuring informed decisions regarding circulating tumor DNA panel testing.

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Angiotensin II (AngII) induces the contraction and proliferation of vascular smooth muscle cells (VSMCs). AngII activates phospholipase C-β (PLC-β), thereby inducing Ca2+ mobilization as well as the production of reactive oxygen species (ROS). Since contraction is a unique property of contractile VSMCs, signaling cascades related to the proliferation of VSMCs may differ. However, the specific molecular mechanism that controls the contraction or proliferation of VSMCs remains unclear. AngII-induced ROS production, migration, and proliferation were suppressed by inhibiting PLC-β3, inositol trisphosphate (IP3) receptor, and NOX or by silencing PLC-β3 or NOX1 but not by NOX4. However, pharmacological inhibition or silencing of PLC-β3 or NOX did not affect AngII-induced VSMC contraction. Furthermore, the AngII-dependent constriction of mesenteric arteries isolated from PLC-β3∆SMC, NOX1-/-, NOX4-/- and normal control mice was similar. AngII-induced VSMC contraction and mesenteric artery constriction were blocked by inhibiting the L-type calcium channel Rho-associated kinase 2 (ROCK2) or myosin light chain kinase (MLCK). The activation of ROCK2 and MLCK was significantly induced in PLC-β3∆SMC mice, whereas the depletion of Ca2+ in the extracellular medium suppressed the AngII-induced activation of ROCK2, MLCK, and vasoconstriction. AngII-induced hypertension was significantly induced in NOX1-/- and PLC-β3∆SMC mice, whereas LCCA ligation-induced neointima formation was significantly suppressed in NOX1-/- and PLC-β3∆SMC mice. These results suggest that PLC-β3 is essential for vascular hyperplasia through NOX1-mediated ROS production but is nonessential for vascular constriction or blood pressure regulation.

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In recent years, next-generation sequencing (NGS)-based genetic testing has become crucial in cancer care. While its primary objective is to identify actionable genetic alterations to guide treatment decisions, its scope has broadened to encompass aiding in pathological diagnosis and exploring resistance mechanisms. With the ongoing expansion in NGS application and reliance, a compelling necessity arises for expert consensus on its application in solid cancers. To address this demand, the forthcoming recommendations not only provide pragmatic guidance for the clinical use of NGS but also systematically classify actionable genes based on specific cancer types. Additionally, these recommendations will incorporate expert perspectives on crucial biomarkers, ensuring informed decisions regarding circulating tumor DNA panel testing.

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BACKGROUND: Since the emergence of coronavirus disease 2019 (COVID-19) across the globe, patients with cancer have been found to have an increased risk of infection with COVID-19 and are highly likely to experience a severe disease course. This study analyzed the clinical outcomes of COVID-19 in patients with non-small cell lung cancer (NSCLC) and identified the risk factors for adverse outcomes.

METHODS: The study included patients diagnosed with COVID-19 between January 2020 and April 2022 at the Samsung Medical Center in Seoul, Republic of Korea, who have a history of NSCLC. The case-fatality rate and risk factors for COVID-19 were analyzed using a machine-learning prediction method. Additionally, the study investigated the effect of COVID-19 on the systemic treatment of patients with advanced-stage NSCLC.

RESULTS: Overall, 1,127 patients were included in this study, with 10.3% of the patients being older than 75 years; of these patients, 51.8% were ex- or current smokers. Among the 584 patients cured after surgery, 91 had stable disease after concurrent chemo-radiotherapy, and 452 had recurrent or metastatic NSCLC. Among 452 patients with recurrent or metastatic NSCLC, 387 received systemic treatment in a palliative setting during COVID-19. Of these, 188 received targeted therapy, 111 received cytotoxic chemotherapy, 63 received immunotherapy +/- chemotherapy, and 26 received other agents. Among them, 94.6% of patients continued systemic treatment after the COVID-19 infection. Only one patient discontinued treatment because of complications of the COVID-19 infection, and 18 patients changed their systemic treatment because of disease progression. The case fatality rates were 0.86% for patients with early-stage NSCLC, 4.4% for patients with locally advanced NSCLC, and 9.96% for patients with advanced NSCLC. The factors associated with fatalities included palliative chemotherapy, type of palliative chemotherapy, age (≥75 years), diabetes, smoking history, history of lung radiotherapy, hypertension, sex, and chronic obstructive pulmonary disease (COPD). The predictive model using logistic regression and eXtreme Gradient Boosting (XGB) performed well [area under the curve (AUC) for logistic regression =0.84 and AUC for XGB =0.84].

CONCLUSIONS: The case fatality rate in patients with NSCLC was 4.8%, while most patients with advanced NSCLC continued to receive systemic treatment. However, patients with risk factors require careful management of COVID-19 complications.

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Lazertinib is a recently developed third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors used for patients with advanced EGFR T790M-positive non-small-cell lung cancer. We evaluated the effectiveness of lazertinib compared with osimertinib using an external control. We obtained individual patient data for the lazertinib arm from the LASER201 trial and the osimertinib arm from registry data at the Samsung Medical Center. In total, 75 and 110 patients were included in the lazertinib and osimertinib groups, respectively. After propensity score matching, each group had 60 patients and all baseline characteristics were balanced. The median follow-up duration was 22.0 and 29.6 months in the lazertinib and osimertinib group, respectively. The objective response rate (ORR) were 76.7% and 86.7% for lazertinib and osimertinib, respectively (p = 0.08). The median progression-free survival (PFS) was 12.3 months (95% confidence interval [CI] 9.5-19.1) and 14.4 months (95% CI 11.8-18.1) for the lazertinib and osimertinib group, respectively (hazard ratio [HR] 0.97; 95% CI 0.64-1.45, p = 0.86). The median overall survival with lazertinib was not reached and that with osimertinib was 29.8 months (HR 0.44; 95% CI 0.25-0.77, p = 0.005). Our study suggests that lazertinib has an ORR and PFS comparable to those of osimertinib and has the potential for superior survival benefits.

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Recently, inverted perovskite solar cells (PeSCs) have witnessed significant advancements; however, their long-term stability remains a challenge because of the oxidation of silver cathodes to form AgI by mobile iodides. To overcome this problem, we propose the integration of an electron-deficient naphthalene diimide-based zwitterion (NDI-ZI) as the cathode interlayer. Compared to the physical ion-blocking layer, it effectively captures ions by forming ionic bonds via electrostatic Coulombic interaction to suppress the migration of iodide and Ag ions. The NDI-ZI interlayer also suppresses the shunt paths and modulates the work function of the Ag electrode by forming interface dipoles, thereby enhancing charge extraction. FA0.85Cs0.15PbI3 based PeSCs incorporating NDI-ZI exhibited a noticeably high power conversion efficiency of up to 23.3% and outstanding stability, maintaining ∼80% of their initial performance over 1500 h at 85 °C and over 500 h under continuous 1-sun illumination. This study highlights the potential of a zwitterionic cathode interlayer in diverse perovskite optoelectronic devices, leading to their improved efficiency and stability.

Abstract

BACKGROUND: Lazertinib is a third-generation tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR-TKI) that selectively inhibit common EGFR mutation and T790M mutation in non-small-cell lung cancer (NSCLC) patients. No previous studies have compared lazertinib to platinum-based chemotherapy. We have compared lazertinib with platinum-based chemotherapy in EGFR-mutated NSCLC patients after previous EGFR-TKI therapy.

METHODS: We retrospectively compared 200 patients from LASER201, LASER301, and LASER-PMS studies to 334 patients who were treated with platinum-based chemotherapy after previous EGFR-TKI from the Samsung Medical Center. After propensity score matching (PSM), we selected 156 patients from each group. The primary outcome was progression-free survival (PFS), with overall survival (OS), objective response rate (ORR), and time to treatment discontinuation (TTD) as secondary outcomes.

RESULTS: The median follow-up of PFS was 15.61 months in the lazertinib group and 21.67 months in the external control group. The PFS was significantly longer in patients who were treated with lazertinib than those treated with platinum-based chemotherapy (10.97 months vs. 5.10 months; adjusted hazard ratio (HR) 0.40; 95% confidence interval (CI), 0.29-0.55; p < 0.01) after PSM. Lazertinib showed superior OS (32.23 months vs. 18.73 months; adjusted HR 0.45; 95% CI, 0.29-0.69; p < 0.001), ORR (64.1% vs. 47.4%), and TTD (11.66 months vs. 6.73 months; adjusted HR 0.54; 95% CI, 0.39-0.75; p < 0.001) compared to platinum-based chemotherapy.

CONCLUSION: Based on this retrospective, external control study, lazertinib has demonstrated significantly better efficacy compared with platinum-based chemotherapy. The external controls provide important context to evaluate efficacy in single-arm studies.

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Abstract

BACKGROUND: The safety of immune-checkpoint inhibitors (ICIs) has not been thoroughly investigated in non-small cell lung cancer (NSCLC) patients with chronic hepatitis B (CHB) or occult hepatitis B infection (OBI). The authors analyzed the incidence of hepatitis B virus (HBV) reactivation, immune-related hepatitis and jaundice in NSCLC patients in a real-world setting.

METHODS: A total of 1277 NSCLC patients treated with ICIs were analyzed. Among them, 52 patients were hepatitis B surface antigen (HBsAg) (+) (group A, CHB), 759 patients were HBsAg (-)/hepatitis B core antibody immunoglobulin G (anti-HBc IgG) (+) (group B, OBI), and 466 patients were HBsAg (-)/anti-HBc IgG (-) (group C). Among the 52 patients with CHB, 38 (73.1%) were receiving antiviral therapy. The primary end point was HBV reactivation, immune-related hepatitis, and jaundice. The secondary end points included other immune-related adverse events and efficacy.

RESULTS: HBV reactivation was observed in two patients (0.2%) who were both in group A (CHB). Among CHB patients who were not receiving antiviral therapy, HBV reactivation was observed in 14.3% (2 of 14 patients). The incidences of immune-related hepatitis and jaundice were comparable among the three groups. The incidence of ≥grade 3 other immune-related adverse events and efficacy were all comparable among the three groups (p > .05 for all comparisons).

CONCLUSIONS: In this large, real-world cohort study, the safety and efficacy of ICIs were comparable in patients with CHB and OBI. HBV reactivation was observed in patients with CHB without antiviral therapy indicating antiviral prophylaxis should be required for them. For patients with OBI, the risk of HBV reactivation was minimal.

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In mammals, hearing loss is irreversible due to the lack of the regenerative capacity of the auditory epithelium. However, stem/progenitor cells in mammalian cochleae may be a therapeutic target for hearing regeneration. The ubiquitin proteasome system plays an important role in cochlear development and maintenance. In this study, we investigated the role of ubiquitin C-terminal hydrolase L1 (UCHL1) in the process of the transdifferentiation of auditory supporting cells (SCs) into hair cells (HCs). The expression of UCHL1 gradually decreased as HCs developed and was restricted to inner pillar cells and third-row Deiters' cells between P2 and P7, suggesting that UCHL1-expressing cells are similar to the cells with Lgr5-positive progenitors. UCHL1 expression was decreased even under conditions in which supernumerary HCs were generated with a γ-secretase inhibitor and Wnt agonist. Moreover, the inhibition of UCHL1 by LDN-57444 led to an increase in HC numbers. Mechanistically, LDN-57444 increased mTOR complex 1 activity and allowed SCs to transdifferentiate into HCs. The suppression of UCHL1 induces the transdifferentiation of auditory SCs and progenitors into HCs by regulating the mTOR pathway.

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Perovskite defects are a major hurdle in the efficiency and stability of perovskite solar cells (PSCs). While various defect passivation materials have been explored, most are insulators that hinder charge transport. This study investigates the potential of two different π-conjugated polyelectrolytes (CPEs), MPS2-TEA and PCPDTBT2-TMA, as semiconducting additives in PSCs. The CPEs differ in electrical conductivity, offering a unique approach to bridge defect mitigation and charge carrier transport. Unlike previous uses of CPEs mainly as interlayers or charge transport layers, we explore their direct effect on defect passivation within a perovskite layer. Secondary ion microscopy reveals the even distribution of CPEs within the perovskite layer and their efficient defect passivation potential is studied through various spectroscopic analyses. Comparing MPS2-TEA and PCPDTBT2-TMA, we find MPS2-TEA to be superior in defect passivation. The highly conductive nature of PCPDTBT2-TMA due to self-doping diminishes its defect passivation ability. The negative sulfonate groups in the side chains of PCPDTBT2-TMA stabilize polarons, reducing defect passivation capability. Finally, the PSCs with MPS2-TEA achieve remarkable power conversion efficiencies (PCEs) of 22.7% for 0.135 cm2 and 20.0% for large-area (1 cm2) cells. Furthermore, the device with MPS2-TEA maintained over 87.3% of initial PCE after 960 h at continuous 1-sun illumination and 89% of PCE after 850 h at 85 °C in a nitrogen glovebox without encapsulation. This highlights CPEs as promising defect passivation additives, unlocking potential for improved efficiency and stability not only in PSCs but also in wider applications.

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PURPOSE: In the treatment of non-small-cell lung cancer (NSCLC) with a driver mutation, the role of anti-PD-(L)1 antibody after tyrosine kinase inhibitor (TKI) remains unclear. This randomized, open-label, multicenter, phase III study evaluates the efficacy of atezolizumab plus bevacizumab, paclitaxel, and carboplatin (ABCP ) in EGFR- or ALK-mutated NSCLC that progressed before TKI therapy.

MATERIALS AND METHODS: We compared the clinical efficacy of ABCP followed by maintenance therapy with atezolizumab plus bevacizumab with pemetrexed plus carboplatin or cisplatin (PC) followed by pemetrexed maintenance. The primary end point was progression-free survival (PFS).

RESULTS: A total of 228 patients with activating EGFR mutation (n = 215) or ALK translocation (n = 13) were enrolled from 16 sites in the Republic of Korea and randomly assigned at 2:1 ratio to either ABCP (n = 154) or PC arm (n = 74). The median follow-up duration was 26.1 months (95% CI, 24.7 to 28.2). Objective response rates (69.5% v 41.9%, P < .001) and median PFS (8.48 v 5.62 months, hazard ratio [HR], 0.62 [95% CI, 0.45 to 0.86]; P = .004) were significantly better in the ABCP than PC arm. PFS benefit increased as PD-L1 expression increased, with an HR of 0.47, 0.41, and 0.24 for PD-L1 ≥1%, ≥10%, and ≥50%, respectively. Overall survival was similar between ABCP and PC arm (20.63 v 20.27 months, HR, 1.01 [95% CI, 0.69 to 1.46]; P = .975). The safety profile of the ABCP arm was comparable with that previously reported, with no additional safety signals, but higher rates of treatment-related adverse events were observed compared with the PC arm.

CONCLUSION: To our knowledge, this study is the first randomized phase III study to demonstrate the clinical benefit of anti-PD-L1 antibody in combination with bevacizumab and chemotherapy in patients with EGFR- or ALK-mutated NSCLC who have progressed on relevant targeted therapy.

Abstract

Diabetes complications are associated with aldose reductase (AR) and advanced glycation end products (AGEs). Using bioassay-guided isolation by column chromatography, 10 flavonoids and one coumarin were isolated from Poncirus trifoliata Rafin and tested in vitro for an inhibitory effect against human recombinant AR (HRAR) and rat lens AR (RLAR). Prunin, narirutin, and naringin inhibited RLAR (IC50 0.48-2.84 μM) and HRAR (IC50 0.68-4.88 μM). Docking simulations predicted negative binding energies and interactions with the RLAR and HRAR binding pocket residues. Prunin (0.1 and 12.5 μM) prevented the formation of fluorescent AGEs and nonfluorescent Nε-(carboxymethyl) lysine (CML), as well as the fructose-glucose-mediated protein glycation and oxidation of human serum albumin (HSA). Prunin suppressed the formation of the β-cross-amyloid structure of HSA. These results indicate that prunin inhibits oxidation-dependent protein damage, AGE formation, and AR, which may help prevent diabetes complications.

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OBJECTIVES: Advanced non-small cell lung cancer patients harboring EGFR mutation or ALK fusion have achieved significant survival benefit with targeted agents. In contrast, EGFR-wild type and ALK negative lung adenocarcinoma still have poor survival outcome. This study assessed the impact of participating in clinical trials on clinical outcomes in patients with EGFR-wild-type and ALK-negative lung adenocarcinoma.

MATERIALS AND METHODS: This study included patients with advanced EGFR-wild-type and ALK-negative lung adenocarcinoma who received systemic treatment between March 2017 and June 2022. We compared clinical outcomes between patients who participated in clinical trials and those treated with standard-of-care (SOC) using propensity score matching (PSM).

RESULTS: Overall, 1,686 patients with EGFR-wild-type and ALK-negative advanced lung adenocarcinoma were included in the final analysis. Of these, 1,380 (81.9 %) received SOC only and 306 (18.1 %) patients were enrolled in at least one clinical trial during their cancer journey. After PSM (1:1), 612 patients were matched to the SOC (n = 306) and clinical trial (n = 306) groups. Among those who participated in clinical trials, 27.8 % and 72.2 % were included in clinical trials involving targeted therapy and immunotherapy respectively. In the clinical trial group, more patients received targeted therapy (31.7 % vs. 5.5 %, p < 0.001) and immunotherapy (88.6 % vs. 62.8 %, p < 0.001) compared to the SOC group. The median overall survival was 17.1 months (95 % confidence interval [CI], 13.2-21.4) in the SOC group and 27.3 months (95 % CI, 22.1-32.4) in the clinical trial group (hazard ratio = 0.71, [95 % CI, 0.58-0.88, P = 0.002]).

CONCLUSIONS: This study demonstrated that participating in clinical trials resulted in a survival benefit that reduced the risk of death by 29.6% compared to receiving SOC in EGFR-wild-type and ALK-negative lung adenocarcinoma.

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Abstract

BACKGROUND: Recent studies have reported the predictive and prognostic value of novel transcriptional factor-based molecular subtypes in small-cell lung cancer (SCLC). We conducted an in-depth analysis pairing multi-omics data with immunohistochemistry (IHC) to elucidate the underlying characteristics associated with differences in clinical outcomes between subtypes.

METHODS: IHC (n = 252), target exome sequencing (n = 422), and whole transcriptome sequencing (WTS, n = 189) data generated from 427 patients (86.4% males, 13.6% females) with SCLC were comprehensively analysed. The differences in the mutation profile, gene expression profile, and inflammed signatures were analysed according to the IHC-based molecular subtype.

FINDINGS: IHC-based molecular subtyping, comprised of 90 limited-disease (35.7%) and 162 extensive-disease (64.3%), revealed a high incidence of ASCL1 subtype (IHC-A, 56.3%) followed by ASCL1/NEUROD1 co-expressed (IHC-AN, 17.9%), NEUROD1 (IHC-N, 12.3%), POU2F3 (IHC-P, 9.1%), triple-negative (IHC-TN, 4.4%) subtypes. IHC-based subtype showing high concordance with WTS-based subtyping and non-negative matrix factorization (NMF) clusterization method. IHC-AN subtype resembled IHC-A (rather than IHC-N) in terms of both gene expression profiles and clinical outcomes. Favourable median overall survival was observed in IHC-A (15.2 months) compared to IHC-N (8.0 months, adjusted HR 2.3, 95% CI 1.4-3.9, p = 0.002) and IHC-P (8.3 months, adjusted HR 1.7, 95% CI 0.9-3.2, p = 0.076). Inflamed tumours made up 25% of cases (including 53% of IHC-P, 26% of IHC-A, 17% of IHC-AN, but only 11% of IHC-N). Consistent with recent findings, inflamed tumours were more likely to benefit from first-line immunotherapy treatment than non-inflamed phenotype (p = 0.002).

INTERPRETATION: This study provides fundamental data, including the incidence and basic demographics of molecular subtypes of SCLC using both IHC and WTS from a comparably large, real-world Asian/non-Western patient cohort, showing high concordance with the previous NMF-based SCLC model. In addition, we revealed underlying biological pathway activities, immunogenicity, and treatment outcomes based on molecular subtype, possibly related to the difference in clinical outcomes, including immunotherapy response.

FUNDING: This work was supported by AstraZeneca, Future Medicine 2030 Project of the Samsung Medical Center [grant number SMX1240011], the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) [grant number 2020R1C1C1010626] and the 7th AstraZeneca-KHIDI (Korea Health Industry Development Institute) oncology research program.

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PURPOSE: Programmed death-1/programmed death-ligand 1 (PD-L1) inhibitors have shown efficacy in metastatic esophageal squamous cell carcinoma (ESCC) therapy. However, data is still limited regarding neoadjuvant immunotherapy for operable ESCC.

MATERIALS AND METHODS: Patients with clinical stage T2 or T3 and N0 ESCC received three cycles of nivolumab therapy every two weeks before surgical resection. The primary endpoint is major pathologic responses (MPR) rate (≤ 10% of residual viable tumor [RVT]).

RESULTS: Total 20 patients completed the planned nivolumab therapy. Among them, 17 patients underwent surgery as protocol, showing MPR in two patients (MPR rate, 11.8%), including one pathologic complete response, on conventional pathologic response evaluation. Pathologic response was re-evaluated using the immune-related pathologic response criteria based on immune-related RVT (irRVT). Three patients were classified as immunologic major pathologic response (iMPR; ≤ 10% irRVT, iMPR rate: 17.6%), five as pathologic partial response (> 10% and < 90% irRVT), and nine as pathologic nonresponse (≥ 90% irRVT). The combined positive score (CPS) for PD-L1 in the baseline samples was predictable for iMPR, with the probability as 37.5% in CPS ≥ 10 (3/8) and 0% in CPS < 10 (0/9).

CONCLUSION: Although the efficacy of neoadjuvant nivolumab therapy was modest in unselected ESCC patients, further researches on neoadjuvant immunotherapy are necessary in patients with PD-L1 expressed ESCC.

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Abstract

Alzheimer's disease (AD) is characterized by the presence of two critical pathogenic factors: amyloid-β (Aβ) and tau. Aβ and tau become neurotoxic aggregates via self-assembly, and these aggregates contribute to the pathogenesis of AD. Therefore, there has been growing interest in therapeutic strategies that simultaneously target Aβ and tau aggregates. Although neferine has attracted attention as a suitable candidate agent for alleviating AD pathology, there has been no study investigating whether neferine affects the modulation of Aβ or tau aggregation/dissociation. Herein, we investigated the dual regulatory effects of neferine on Aβ and tau aggregation/dissociation. We predicted the binding characteristics of neferine to Aβ and tau using molecular docking simulations. Next, thioflavin T and atomic force microscope analyses were used to evaluate the effects of neferine on the aggregation or dissociation of Aβ42 and tau K18. We verified the effect of neferine on Aβ fibril degradation using a microfluidic device. In addition, molecular dynamics simulation was used to predict a conformational change in the Aβ42-neferine complex. Moreover, we examined the neuroprotective effect of neferine against neurotoxicity induced by Aβ and tau and their fibrils in HT22 cells. Finally, we foresaw the pharmacokinetic properties of neferine. These results demonstrated that neferine, which has attracted attention as a potential treatment for AD, can directly affect Aβ and tau pathology.

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BACKGROUND: Limited disease (LD) small cell lung cancer (SCLC) treated with definitive concurrent chemoradiotherapy (CCRT) potentially experience disease recurrence. We investigated the feasibility of circulating-tumor DNA (ctDNA)-based genomic and fragmentome analyses to assess the risk of recurrence.

METHODS: Targeted sequencing was conducted using pre-treatment and on-treatment blood samples from definitive CCRT-treated patients with LD-SCLC (n=50). Based on 12-month recurrence-free survival (RFS), patients were categorized into persistent-response (PeR, n=29) and non-PeR (n=21) groups. Fragmentome analysis was conducted using ctDNA fragments of different lengths: P1 (100-155 bp) and P2 (160-180 bp).

RESULTS: Patients with TP53 (n=15) and RB1 (n=11) mutation in on-treatment samples demonstrated significantly shorter RFS than patients with wild-type (WT) (P=0.05, P=0.0014, respectively). Fragmentome analysis of all available on-treatment samples (n=26) revealed that the non-PeR group (n=10) had a significantly higher P1 range (P=0.003) and lower P2 range (P=0.002). The areas under the curves for P1, P2, and the fragmentation ratio (P1/P2) in distinguishing the PeR and non-PeR were 0.850, 0.725, and 0.900, respectively. Using optimal cut-off, longer RFSs were found with the low-fragmentation-ratio group than with the high-fragmentation-ratio group (not reached vs. 7.6 months, P=0.002). Patients with both WT RB1 and a low-fragmentation-ratio (n=10) showed better outcomes than patients with both mutated RB1 and a high-fragmentation-ratio (n=10; hazard ratio, 7.55; 95% confidence interval: 2.14-26.6; P=0.002).

CONCLUSIONS: RB1 mutations and high fragmentation ratios correlated with early disease recurrence. Analyzing ctDNA could help in predicting early treatment failure and making clinical decisions for high-risk patients.

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BACKGROUND: Based on a high incidence of genomic alteration in the cell cycle and DNA damage and response (DDR)-related pathways in small cell lung cancer (SCLC), the clinical efficacy of the DDR-targeting agent olaparib (PARP inhibitor) as monotherapy and in combination with ceralasertib (ATR inhibitor) in relapsed or refractory SCLC was evaluated.

METHODS: As part of a phase 2 biomarker driven umbrella study, patients with SCLC and predefined DDR gene alterations who failed to benefit from prior platinum-based regimens were allocated to the olaparib monotherapy arm and nonbiomarker-selected patients were allocated to the olaparib and ceralasertib combination arm.

RESULTS: In the olaparib monotherapy arm (n = 15), the objective response rate was 6.7% (one partial response), and the disease control rate was 33.3%, including three patients with stable disease. The median progression-free survival was 1.3 months (95% CI, 1.2-NA). In the combination arm (n = 26), the objective response rate and disease control rate were 3.8% and 42.3%, respectively, with one partial response and 10 patients with stable disease. The median progression-free survival was 2.8 months (95% CI, 1.8-5.4). Treatment was generally well tolerated except for one fatal case of neutropenic fever in the combination arm.

CONCLUSIONS: Targeting DDR pathways with olaparib as a single agent or in combination with ceralasertib did not meet the predefined efficacy end point. However, disease stabilization was more evident in the combination arm. Further investigation of the combination of olaparib in SCLC should be performed with diverse combinations and patient selection strategies to maximize efficacy.

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IMPORTANCE: Valuable evidence regarding clinical characteristics, treatments, and outcomes for non-small cell lung cancer (NSCLC) is limited to individual hospital databases or national-level registries. The common data and federated analysis framework developed through the Extensible Platform for Observational Research in Lung Cancer (EXPLORE-LC) initiative allows for research across multiple high-quality data sources, which may provide a deeper understanding of the NSCLC landscape and identification of unmet needs of subpopulations.

OBJECTIVE: To describe clinical characteristics, initial treatment patterns, subsequent treatment, and overall survival (OS) of patients with NSCLC in South Korea.

DESIGN, SETTING, AND PARTICIPANTS: This multicenter cohort study included patients aged 18 years and older who were diagnosed with NSCLC between 2014 and 2019 and followed up until March 2020 at 3 tertiary hospitals in South Korea. Clinical data were collected using a common data model and clinical data warehouse. Patients who had an initial diagnosis of nonsquamous (NSQ) or squamous (SQ) NSCLC and who had received at least 1 treatment for NSCLC were included in the study. Data were analyzed from June through November 2022.

MAIN OUTCOMES AND MEASURES: The primary outcome was clinical OS for patients with NSCLC. Secondary outcomes were clinical characteristics and treatment patterns subsequent to the diagnosis of NSCLC.

RESULTS: Among 22 101 patients with NSCLC who received anticancer treatment analyzed in this study, 17 350 patients (78.5%) had NSQ and 4751 patients (21.5%) had SQ NSCLC. Clinical characteristics and outcomes and treatment patterns were assessed for 13 084 patients with NSQ cancer who had known EGFR and ALK status (75.4%; mean [SD] 62.2 [10.5] years; 6552 males [50.1%]) and all 4751 patients with SQ cancer (mean [SD] age, 67.1 [8.6] years; 4427 males [93.2%]). More than half of patients with NSQ cancer were never smokers (7399 patients [56.6%]). Patients with SQ cancer were mostly males and former or current smokers (4235 patients [89.1%]) and were diagnosed at a later clinical stage than patients with NSQ cancer (eg, stage I: 1165 patients [24.5%] vs 5388 patients [41.2%]). Patients with EGFR-positive and ALK-positive NSQ cancer diagnosed between 2017 and 2019 had better median OS than similar patients diagnosed between 2014 and 2016 (EGFR-positive: not reached [95% CI, 35.9 months to not reached] vs 28.4 months [95% CI, 25.8 to 30.0 months]; P < .001; ALK-positive: not reached [95% CI, not reached] vs 49.5 months [95% CI, 35.1 months to not reached]; P < .001). No significant difference was observed in OS from first-line treatment for patients with SQ cancer.

CONCLUSIONS AND RELEVANCE: This study, which pooled medical data from multiple clinical data warehouses to produce a large study cohort, may provide meaningful insights into the clinical practice of NSCLC and underscores the value of a common data model approach. The analyzable dataset may hold great promise for future comprehensive identification of subpopulations and unmet needs.

Abstract

INTRODUCTION: Numerous studies have suggested high concordance between tissue and circulating tumor DNA (ctDNA) comprehensive genomic profiling (CGP) tests but only few of them focused on fusions. In addition, atypical breakpoints occasionally detected from DNA-based fusion detection make interpretation difficult, and their clinical significance remains unclear. This study evaluated the clinical utility of ctDNA CGP for fusion detection.

METHODS: The results of ctDNA CGP tests performed on patients with stage IV non-small cell lung cancer during routine clinical care were retrospectively reviewed. The concordance between ctDNA CGP and combined tissue test results was analyzed using CGP, immunohistochemistry, fluorescence in situ hybridization, and reverse transcription polymerase chain reaction. The clinical significance of fusions detected by ctDNA CGP, including those with atypical breakpoints at the DNA level, was assessed.

RESULTS: In total, 264 patients were tested with ctDNA CGP. Fusions were detected in 27 patients (10.2%), and the fusion drivers were RET (n=12, 4.6%), ALK (n=9, 3.4%), ROS1 (n=4, 1.5%), and FGFR2 (n=2, 0.8%). The overall prevalence of fusion in tissue CGP was comparable to that in ctDNA CGP. A total of 371 ctDNA-tissue test pairs were available, and the overall positive and negative percent agreement rates were 92.9% (13/14) and 100.0% (357/357), respectively. One ALK IHC-positive and ctDNA CGP-negative case did not respond to ALK-targeted therapy. Response to targeted therapy was assessed in 16 patients, and a partial response was achieved in all patients, including four with atypical breakpoints.

CONCLUSION: Fusion detection using ctDNA CGP showed high concordance with tissue tests and accuracy in predicting therapeutic responses in patients with non-small cell lung cancer. ctDNA CGP may provide an important diagnostic tool for fusion detection.

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INTRODUCTION: This study created and validated a scale to measure the level of suicide crisis among international students attending South Korean universities.

METHODS: Study 1 developed questions and constructed the components of the scale using an initial survey of 248 people and exploratory factor analysis. Study 2 validated the scale using a second survey of 340 participants and confirmatory factor analysis.

RESULTS: The results showed that 21 items were confirmed in six factors, which include lack of social support, burdensomeness, maladaptation to Korean culture, academic maladjustment, suicidal thoughts, and suicide risk.

DISCUSSION: We verified the convergent validity, criterion validity, and reliability of the scale. The significance and implications of this study are presented, along with suggestions for future research.

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PURPOSE: Alectinib and brigatinib are second-generation anaplastic lymphoma receptor tyrosine kinases (ALKs) that are widely used as first-line therapy for treating ALK-positive advanced non-small cell lung cancer (NSCLC). Given the lack of a head-to-head comparison of these drugs as first-line therapies, this retrospective observational study aimed to compare the real-world efficacy and safety of alectinib and brigatinib.

MATERIALS AND METHODS: Patients who received alectinib or brigatinib as the first-line treatment for ALK-positive advanced NSCLC were evaluated for clinical outcomes of objective response rate (ORR), intracranial ORR, time to next treatment (TTNT), progression-free survival (PFS), overall survival (OS), and safety profiles.

RESULTS: Of 208 patients who received either alectinib or brigatinib as a first-line treatment, 176 received alectinib and 32 received brigatinib. At the data cutoff point, the median follow-up duration was 16.5 months (95% confidence interval [CI], 14.7 to 18.3) in the brigatinib group and 27.5 months (95% CI, 24.6 to 30.4) in the alectinib group. The ORR was 92.5% with alectinib and 93.8% for brigatinib. The intracranial ORR rates were 92.7% (38/41) and 100% (10/10), respectively. The rate of PFS at 12 months was comparable between the alectinib group and the brigatinib groups (84.4% vs. 84.1%, p=0.64), and the median TTNT, PFS, and OS were not reached in either group. Treatment-related adverse events were usually mild, and treatment discontinuation due to adverse events was rare (alectinib 4.5% vs. brigatinib 6.25%).

CONCLUSION: Alectinib and brigatinib had similar clinical benefits when used as the first-line treatment of NSCLC patients with ALK rearrangement in the real world.

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BACKGROUND: In non-small cell lung cancer (NSCLC), the epidermal growth factor receptor (EGFR) mutation is a representative oncogenic driver mutation. Only about 12% of EGFR mutation patients have the exon 20 insertion mutation, which is the third most frequent mutation among EGFR mutation NSCLC. Amivantamab, an EGFR and MET proto-oncogene, receptor tyrosine kinase (MET) bispecific antibody, was approved for NSCLC patients with the EGFR exon 20 insertion (E20I) mutation. In this study, we described the real-world, single-center efficacy and safety data of amivantamab in E20I mutation patients.

METHODS: This study included metastatic NSCLC patients with EGFR E20I mutations. From January 2018 to June 2022, patients with EGFR E20I mutations who were treated with amivantamab were analyzed at Samsung Medical Center as part of the clinical trial or the early access program (EAP). We collected the patients' characteristics [age, sex, smoking history, location of mutation, sites of metastasis, programmed death-ligand 1 (PD-L1) expression status, etc.] and analyzed progression-free survival (PFS) and overall survival (OS) stratified by PD-L1 expression status, co-mutation such as tumor protein p53 (TP53), and metastasis sites.

RESULTS: A total of 42 patients were analyzed, of which 16 patients were enrolled in the phase 1 study, and 26 patients received amivantamab through EAP. There were 14 (33%) patients with partial remission, 18 (43%) patients with stable disease, and 10 (24%) patients with disease progression. The objective response rate (ORR) was 33%, and the disease control rate (DCR) was 76%. PFS was analyzed by dividing the near and far loop for 31 patients whose mutation location was known. The two groups had no statistically significant difference in PFS [median (range): 11.8 (2.3-21.3) vs. 11.3 (3.4-19.2) months, P=0.69]. For 29 patients with TP53 mutation data, there was no significant difference in PFS between the two groups [median (range): 5.9 (0-18.0) vs. 12.6 (6.9-18.3) months, P=0.11]. When analyzing PFS in 37 patients with PD-L1 expression data, PD-L1 (+) patients showed a poor prognosis [median (range): 11.3 (5.0-17.6) vs. 19.5 (5.3-33.7) months, P=0.04; hazard ratio (HR), 0.44; 95% confidence interval (CI): 0.20-0.98].

CONCLUSIONS: The efficacy of amivantamab was confirmed for the real-world population for EGFR E20I-mutated NSCLC. PD-L1 status could be a poor predictive factor, which should be further validated.

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PURPOSE: We aimed to compare the oncological outcomes and toxicities of definitive proton beam therapy (PBT) and photon beam therapy in patients with limited-stage small cell lung cancer (LS-SCLC).

MATERIALS AND METHODS: We retrospectively reviewed 262 patients with newly diagnosed LS-SCLC who underwent definitive PBT (n = 20; proton group) or photon beam therapy (n = 242; photon group) with concurrent chemotherapy between January 2016 and February 2021 and compared overall survival (OS), progression-free survival (PFS), dose-volume parameters, and toxicities between the groups.

RESULTS: The median follow-up duration was 24.5 months (range, 3.7 to 78.7). Baseline lung function was significantly worse and clinical target volume (CTV) was larger in the proton group (CTV: 296.6 vs. 215.3 mL; p = 0.080). The mean lung V10 was 37.7% ± 16.8% and 51.6% ± 24.5% in the proton and photon groups, respectively (p = 0.002). Two-year OS and PFS rates were 57.2% and 35.7% in the proton group and 65.3% and 40.8% in the photon group, respectively (p = 0.542 and 0.748, respectively). Grade ≥2 radiation pneumonitis and esophagitis occurred in 5 (25.0%) and 7 (35.0%) PBT-treated patients and 66 (27.3%) and 40 (16.5%) photon beam therapy-treated patients, respectively (p = 0.826 and 0.062, respectively).

CONCLUSION: Although the proton group had poorer lung function and a larger CTV than that in the photon group, both groups exhibited comparable treatment outcomes and radiation-related toxicities in LS-SCLC. PBT may be a valuable therapeutic modality in patients with poor pulmonary function or extensive disease burden owing to its lung-sparing ability.

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INTRODUCTION: Dacomitinib showed superior progression-free survival (PFS) and overall survival compared to gefitinib in patients with advanced non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations in the ARCHER1050 study. However, because that study did not include patients with brain metastases, the efficacy of dacomitinib in patients with brain metastases has not been clarified.

PATIENTS AND METHODS: This single-arm phase II study enrolled 30 patients with treatment-naïve advanced NSCLC harboring activating EGFR mutations from January 2021 to June 2021 and started them on dacomitinib (45 mg/day). All patients had non-irradiated brain metastases with a diameter of ≥5 mm. The primary endpoint was confirmed intracranial objective response rate (iORR).

RESULTS: Patients had exon 19 deletions (46.7%) and L858R mutations in exon 21 (55.3%). The confirmed iORR was 96.7% (29/30), with an intracranial complete response of 63.3%. Median intracranial PFS (iPFS) was not reached, with 12- and 18-month iPFS rates of 78.6% [95% confidence interval (CI) 64.8% to 95.4%] and 70.4% (95% CI 54.9% to 90.1%), respectively. In the competing risk analysis, the 12-month cumulative incidence of intracranial progression was 16.7%. Regarding the overall efficacy for intracranial and extracranial lesions, the overall ORR was 96.7%, and the median PFS was 17.5 months (95% CI 15.2 months-not reached). Grade 3 or higher treatment-related adverse events were reported in 16.7% of patients, and 83.3% required a reduced dacomitinib dose to manage adverse events. However, none permanently discontinued dacomitinib treatment due to treatment-related adverse events.

CONCLUSIONS: Dacomitinib has outstanding intracranial efficacy in patients with EGFR-mutant NSCLC with brain metastases.

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INTRODUCTION: While the efficacy of immune checkpoint inhibitors (ICIs) in treating non-small cell lung cancer (NSCLC) patients with actionable genetic alterations (AGAs) is modest, certain patients demonstrate improved survival. Thus, this study aimed to evaluate the benefits of ICIs in NSCLC patients with diverse AGAs and verify the predictive biomarkers of ICI efficacy.

METHODS: From January 2018 to July 2022, this study compared the progression-free survival (PFS) of NSCLC patients with different AGAs treated with ICI monotherapy as second- or later-line therapy at Samsung Medical Center. To ascertain the predictors of ICIs efficacy, we adjusted ICIs' effects on PFS in terms of clinical and molecular biomarkers.

RESULTS: EGFR (46.0%) was the most prevalent mutation in 324 patients. In multivariate analysis, PD-L1 positivity (tumor proportion score (TPS) ≥ 1%) (HR = 0.41) and the use of steroids for immune-related adverse events (HR = 0.46) were positive factors for ICI therapy in the AGAs group. Co-existing mutation of STK11 with KRAS mutation (HR = 4.53) and TP53 with MET mutation (HR = 9.78) was negatively associated with survival.

CONCLUSIONS: The efficacy of ICI treatment varied across AGA subtypes, but patients with KRAS, MET, and BRAF mutations demonstrated relatively long-duration benefits of ICI therapy. PD-L1 was a significant positive predictive biomarker in all AGA groups.

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Natural flavone and isoflavone analogs such as 3',4',7-trihydroxyflavone (1), 3',4',7-trihydroxyisoflavone (2), and calycosin (3) possess significant neuroprotective activity in Alzheimer's and Parkinson's disease. This study highlights the in vitro human monoamine oxidase (hMAO) inhibitory potential and functional effect of those natural flavonoids at dopamine and serotonin receptors for their possible role in neuroprotection. In vitro hMAO inhibition and enzyme kinetics studies were performed using a chemiluminescent assay. The functional effect of three natural flavonoids on dopamine and serotonin receptors was tested via cell-based functional assays followed by a molecular docking simulation to predict interactions between a compound and the binding site of the target protein. A forced swimming test was performed in the male C57BL/6 mouse model. Results of in vitro chemiluminescent assays and enzyme kinetics depicted 1 as a competitive inhibitor of hMAO-A with promising potency (IC50 value: 7.57 ± 0.14 μM) and 3 as a competitive inhibitor of hMAO-B with an IC50 value of 7.19 ± 0.32 μM. Likewise, GPCR functional assays in transfected cells showed 1 as a good hD4R antagonist. In docking analysis, these active flavonoids interacted with a determinant-interacting residue via hydrophilic and hydrophobic interactions, with low docking scores comparable to reference ligands. The post-oral administration of 1 to male C57BL/6 mice did not reduce the immobility time in the forced swimming test. The results of this study suggest that 1 and 3 may serve as effective regulators of the aminergic system via hMAO inhibition and the hD4R antagonist effect, respectively, for neuroprotection. The route of administration should be considered.

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Icariin, a major bioactive compound found in the Epimedium genus, has been reported to exert protective effects against neurodegenerative disorders. In the current study, we aimed to investigate the regulatory effect of icariin and its active metabolites (icariside II and icaritin) against prime G-protein-coupled receptor targets, considering their association with neuronal disorders. Icariside II exhibited selective agonist activity towards the dopamine D3 receptor (D3R), with half-maximal effective concentrations of 13.29 μM. Additionally, they effectively inhibited the specific binding of radioligands to D3R. Molecular docking analysis revealed that icariside II potentially exerts its agonistic effect through hydrogen-bonding interaction with Asp110 of the D3R, accompanied by negative binding energy. Conversely, icaritin demonstrated selective antagonist effects on the muscarinic acetylcholine M2 receptor (M2R). Radioligand binding assay and molecular docking analysis identified icaritin as an orthosteric ligand for M2R. Furthermore, all three compounds, icariin and its two metabolites, successfully mitigated MK-801-induced schizophrenia-like symptoms, including deficits in prepulse inhibition and social interaction, in mice. In summary, these findings highlight the potential of icariin and its metabolites as promising lead structures for the discovery of new drugs targeting cognitive and neurodegenerative disorders.

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BACKGROUND: Salivary duct carcinoma (SDC) is uncommon but is the most aggressive subtype of salivary gland carcinomas. The high positivity rate for human epidermal growth factor receptor 2 (HER2) led to an investigation of the efficacy of HER2-targeted agents. Docetaxel-PM (polymeric micelle) is a low-molecular-weight, nontoxic, biodegradable, and docetaxel-loaded micellar formulation. Trastuzumab-pkrb is a biosimilar to trastuzumab.

METHODS: This was a multicenter, single-arm, open-label phase 2 study. Patients with HER2-positive (immunohistochemistry [IHC] score of ≥2+ and/or HER2/chromosome enumeration probe 17 [CEP17] ratio of ≥2.0) advanced SDCs were enrolled. Patients received docetaxel-PM (75 mg/m2 ) and trastuzumab-pkrb (8 mg/kg in the first cycle and 6 mg/kg in subsequent cycles) every 3 weeks. Primary end point was objective response rate (ORR).

RESULTS: A total of 43 patients were enrolled. The best objective responses were partial response in 30 (69.8%) patients and stable disease in 10 (23.3%) patients, leading to an ORR of 69.8% (95% confidence interval [CI], 53.9-82.8) and a disease control rate of 93.0% (80.9-98.5). Median progression-free survival, duration of response, and overall survival were 7.9 (6.3-9.5), 6.7 (5.1-8.4), and 23.3 (19.9-26.7) months, respectively. Patients with HER2 IHC score of 3+ or HER2/CEP17 ratio ≥2.0 demonstrated better efficacies compared to those with HER2 IHC score of 2+. Thirty-eight (88.4%) patients experienced treatment-related adverse events (TRAE). Because of TRAE, nine (20.9%), 14 (32.6%), and 19 (44.2%) patients required temporary discontinuation, permanent discontinuation, or dose reduction, respectively.

CONCLUSIONS: The combination of docetaxel-PM and trastuzumab-pkrb demonstrated promising antitumor activity with a manageable toxicity profile in HER2-positive advanced SDC.

PLAIN LANGUAGE SUMMARY: Salivary duct carcinoma (SDC) is uncommon but is the most aggressive subtype of salivary gland carcinomas. SDC shares morphological and histological similarities with invasive ductal carcinoma of breast, which led to an investigation of hormonal receptor and human epidermal growth factor receptor 2 (HER2)/neu expression status in SDC. In this study, patients with HER2-positive SDC were enrolled and treated with combination of docetaxel-polymeric micelle and trastuzumab-pkrb. Promising antitumor activities were shown with objective response rate of 69.8%, disease control rate of 93.0%, median progression-free survival of 7.9 months, median duration of response of 6.7 months, and median overall survival of 23.3 months.

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PURPOSE: Rearranged during transfection (RET) gene rearrangement is a well-known driver event in non-small cell lung cancer (NSCLC). Pralsetinib is a selective inhibitor of RET kinase and has shown efficacy in oncogenic RET-altered tumors. This study evaluated the efficacy and safety of expanded access program (EAP) use of pralsetinib in pretreated, advanced NSCLC patients with RET rearrangement.

MATERIALS AND METHODS: Patients who received pralsetinib as part of the EAP at Samsung Medical Center were evaluated through a retrospective chart review. The primary endpoint was overall response rate (ORR) per the Response Evaluation Criteria in Solid Tumors (RECIST) ver. 1.1 guidelines. Secondary endpoints were duration of response, progression-free survival (PFS), overall survival (OS), and safety profiles.

RESULTS: Between April 2020 and September 2021, 23 of 27 patients were enrolled in the EAP study. Two patients who were not analyzed due to brain metastasis and two patients whose expected survival was within 1 month were excluded from the analysis. After a median follow-up period of 15.6 months (95% confidence interval [CI], 10.0 to 21.2), ORR was 56.5%, the median PFS was 12.1 months (95% CI, 3.3 to 20.9), and the 12-month OS rate was 69.6%. The most frequent treatment-related adverse events (TRAEs) were edema (43.5%) and pneumonitis (39.1%). A total of 8.7% of patients experienced extra-pulmonary tuberculosis. TRAEs with a common grade of three or worse were neutropenia (43.5%) and anemia (34.8%). Dose reduction was required in nine patients (39.1%).

CONCLUSION: Pralsetinib presents a clinical benefit when used in patients with RET-rearranged NSCLC, consistent with a pivotal study.

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PURPOSE: This phase II study investigated whether durvalumab/tremelimumab with proton therapy improves the objective response rate (ORR), overall survival (OS), and progression-free survival (PFS) in heavily treated recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) patients.

MATERIALS AND METHODS: Patients who previously received more than one chemotherapy, including at least one platinum-based regimen, and who had at least two measurable lesions were enrolled. Patients received 1,500 mg durvalumab intravenously combined with 75 mg tremelimumab intravenously every 4 weeks for four cycles followed by 1,500 mg durvalumab every 4 weeks. After one cycle of the durvalumab/tremelimumab treatment, proton therapy was given with a total dose of 25 Gy in 5 Gy daily fractions to one of the measurable lesions. We also assessed the ORR in the target lesion outside the radiation field to evaluate the abscopal effect.

RESULTS: Thirty-one patients were enrolled between March 2018 and July 2020. With 8.6 months of follow-up, the ORR was 22.6% (7/31), including one complete response and six partial responses. The median OS was 8.4 months (95% confidence interval [CI], 2.5 to 14.3) and the median PFS was 2.4 months (95% CI, 0.6 to 4.2). Among the 23 evaluable patients who completed proton therapy, the ORR was 30.4% (7/23). The median OS was 11.1 months (95% CI, 6.5 to 15.8), and the median PFS was 3.7 months (95% CI, 1.6 to 5.7). Grade 3 or higher adverse events were observed in six patients (19.4%) as follows: anemia (n=1), constipation (n=1), electrolyte imbalances (n=2), hyperglycemia (n=1), and pneumonia (n=1).

CONCLUSION: The combination of durvalumab/tremelimuab with proton therapy was tolerated well and had encouraging anti-tumor efficacy in non-irradiated tumor lesions of heavily treated HNSCC patients.

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BACKGROUND: Lazertinib is a third generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) designed to overcome EGFR T790M mutation. Currently, lazertinib is approved for usage in the acquired EGFR T790M mutation population based on promising clinical and safety profiles. In this study, we evaluated the clinical outcomes of lazertinib in acquired EGFR T790M mutated non-small cell lung cancer (NSCLC) patients in a real-world clinical setting.

METHODS: Clinical outcomes of 103 patients treated with lazertinib, from July 2021 to August 2022, for NSCLC with acquired EGFR T790M mutation were retrospectively analyzed. EGFR T790M mutation was confirmed using either a cell-free EGFR test (48.5%) or a tissue-based test (51.5%).

RESULTS: The median follow-up duration was 11.4 months [95% confidence interval (CI): 10.4-13.1], and 58.3% of patients remained on treatment at the time point of data analysis. The objective response rate was 72.8%. The median progression-free survival (PFS) was not reached, and the PFS rates at 6 and 12 months were 81.7% and 65.1%, respectively. The median PFS in a subgroup treated with lazertinib based on T790M-positive tissue was significantly longer than that in a subgroup treated based on T790M-positive plasma (not reached vs. 14.5 months) (hazard ratio, 0.43; 95% CI: 0.21-0.87). Related to adverse events, there was no treatment-related mortality. However, the lazertinib dose was adjusted in 39 patients (37.9%), including 10 patients (9.7%) with permanent discontinuation. Peripheral sensory-motor related adverse events were observed in 65 patients (63.1%) (paresthesia: n=58; muscle cramping: n=24), leading to dose reduction and permanent discontinuation in 17 (16.5%) and 5 (4.9%) patients, respectively. There was no difference in PFS between the groups with and without dose-adjustment (P=0.40).

CONCLUSIONS: Our result demonstrates the real-world clinical efficacy of lazertinib in acquired EGFR T790M mutation. Although dose reduction due to adverse events was not uncommon, it did not impair clinical efficacy of lazertinib.

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INTRODUCTION: For patients with early stage EGFR-mutant-positive (EGFR-M+) NSCLC, curative surgery followed by adjuvant chemotherapy is considered the standard of care. This study evaluated the feasibility and efficacy of longitudinal monitoring of circulating tumor DNA (ctDNA) as a valuable biomarker for early detection of minimal residual disease (MRD) and provides identification of the group at high risk for recurrence in resected stages I to IIIA EGFR-M+ NSCLC.

METHODS: Between August 2015 and October 2017, a total of 278 patients with curative resected, stages I to IIIA (American Joint Committee on Cancer seventh version) common EGFR-M+ NSCLC were analyzed. Radiological follow-up was accompanied with longitudinal monitoring of ctDNA using a droplet-digital polymerase chain reaction from baseline (preoperative), 4 weeks after curative surgery, and follow-up per protocol until 5 years. The primary outcomes were disease-free survival (DFS) according to the status of ctDNA positivity at landmark points and the sensitivity of longitudinal monitoring of ctDNA.

RESULTS: Among 278 patients, preoperative baseline ctDNA was detected in 67 (24%) patients: 23% (stage IA), 18% (IB), 18% (IIA), 50% (IIB), and 42% (IIIA) (p = 0.06). Of patients with baseline ctDNA, 76% (51 of 67) had clearance at 4 weeks after surgery (postoperative). Patients were classified into the following three groups; group A, baseline ctDNA negative (n = 211) versus group B, baseline ctDNA positive but postoperative MRD negative (n = 51) versus group C, baseline ctDNA positive and postoperative MRD positive (n = 16). The 3-year DFS rate was significantly different among the three groups (84% for group A, 78% for group B, and 50% for group C, p = 0.02). After adjusting for clinicopathologic variables, ctDNA still remains an independent risk factor for DFS along with stage (p < 0.001) and micropapillary subtype (p = 0.02). With longitudinal monitoring of ctDNA, MRD was detected before radiological recurrence in 69% of patients with exon 19 deletion and in 20% with L858R mutation.

CONCLUSIONS: These results suggest that patients with baseline ctDNA-positive or MRD-positive status were associated with poor DFS in curative resected stages I to IIIA EGFR-M+ NSCLC and that longitudinal monitoring of ctDNA, a noninvasive method, might be useful to detect early recurrence before radiological recurrence.

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More people use the internet for medical information, especially YouTube. Nevertheless, no study has been conducted to analyze the quality of YouTube videos about tinnitus in Korea. This study aims to review the contents and quality of YouTube videos on tinnitus. The top 100 Korean YouTube videos on tinnitus were reviewed by a tinnitus expert. This study assessed video details: title, creator, length, and popularity indicators-subscribers, views, and likes. The contents of the video clips were analyzed to determine the relevance, understandability, actionability, and quality of information. Out of 100 tinnitus videos, 27 were created by otolaryngologists, 25 by traditional Korean medicine doctors, 25 by other medical professionals, and 3 by lay persons. Sensorineural tinnitus was frequently dealt, and hearing loss, stress, and noise were introduced as main causes of tinnitus. Otolaryngologists' videos covered verified treatments, but others suggested unproven therapies including herbal medicine or acupressure. Otolaryngologists' videos showed significantly higher understandability and quality of information compared to others (p < 0.001). This study found that tinnitus YouTube videos frequently present low-quality and incorrect material, which could have an adverse effect on patients. Results highlight the need for tinnitus specialists to provide accurate information.

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BACKGROUND: We evaluated the therapeutic efficacy of GC1118, a novel anti-epidermal growth factor receptor (EGFR) monoclonal antibody, in recurrent glioblastoma (GBM) patients with EGFR amplification.

METHODS: This study was a multicenter, open-label, single-arm phase II trial. Recurrent GBM patients with EGFR amplification were eligible: EGFR amplification was determined using fluorescence in situ hybridization analysis when a sample had both the EGFR/CEP7 ratio of ≥2 and a tight cluster EGFR signal in ≥10% of recorded cells. GC1118 was administered intravenously at a dose of 4 mg/kg once weekly. The primary endpoint was the 6-month progression-free survival rate (PFS6). Next-generation sequencing was performed to investigate the molecular biomarkers related to the response to GC1118.

RESULTS: Between April 2018 and December 2020, 21 patients were enrolled in the study and received GC1118 treatment. Eighteen patients were eligible for efficacy analysis. The PFS6 was 5.6% (95% confidence interval, 0.3%-25.8%, Wilson method). The median progression-free survival was 1.7 months (range: 28 days-7.2 months) and median overall survival was 5.7 months (range: 2-22.0 months). GC1118 was well tolerated except skin toxicities. Skin rash was the most frequent adverse event and four patients experienced Grade 3 skin-related toxicity. Genomic analysis revealed that the immune-related signatures were upregulated in patients with tumor regression.

CONCLUSION: This study did not meet the primary endpoint (PFS6); however, we found that immune signatures were significantly upregulated in the tumors with regression upon GC1118 therapy, which signifies the potential of immune-mediated antitumor efficacy of GC1118.

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Metal-halide perovskite nanocrystals (NCs) have emerged as suitable light-emitting materials for light-emitting diodes (LEDs) and other practical applications. However, LEDs with perovskite NCs undergo environment-induced and ion-migration-induced structural degradation during operation; therefore, novel NC design concepts, such as hermetic sealing of the perovskite NCs, are required. Thus far, viable synthetic conditions to form a robust and hermetic semiconducting shell on perovskite NCs have been rarely reported for LED applications because of the difficulties in the delicate engineering of encapsulation techniques. Herein, a highly bright and durable deep-blue perovskite LED (PeLED) formed by hermetically sealing perovskite NCs with epitaxial ZnS shells is reported. This shell protects the perovskite NCs from the environment, facilitates charge injection/transport, and effectively suppresses interparticle ion migration during the LED operation, resulting in exceptional brightness (2916 cd m-2 ) at 451 nm and a high external quantum efficiency of 1.32%. Furthermore, even in the unencapsulated state, the LED shows a long operational lifetime (T50 ) of 1192 s (≈20 min) in the air. These results demonstrate that the epitaxial and hermetic encapsulation of perovskite NCs is a powerful strategy for fabricating high-performance deep-blue-emitting PeLEDs.

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PURPOSE: To investigate whether the trajectories of saccadic eye movements (SEMs) significantly differ between glaucoma patients and controls.

METHODS: SEMs were recorded by video-based infrared oculography in 53 patients with glaucoma and 41 age-matched controls. Participants were asked to bilaterally view 24°-horizontal, 14°-vertical, and 20°-diagonal eccentric Goldmann III-sized stimuli. SEMs were evaluated with respect to the saccadic reaction time (SRT), the mean velocity, amplitude, and two novel measures: departure angle (DA) and arrival angle (AA). These parameters were compared between the groups and the associations of SEM parameters with glaucoma parameters and integrated visual field defects were investigated.

RESULTS: Glaucoma patients exhibited increased mean SRT, DA, and AA values compared with controls for 14°-vertical visual targets (P = 0.05, P < 0.01, and P < 0.01, respectively). The SRT, DA, and AA were significantly associated with the mean and pattern standard deviations of perimetry and with the mean RNFL thickness by OCT (all P < 0.001). Glaucoma was associated with the AA (P = 0.05) and both the SRT (P = 0.01) and DA (P = 0.04) were associated with integrated visual field defects.

CONCLUSIONS: The saccadic trajectories of glaucoma patients depart in an erroneous path and compensate the disparity by deviating the trajectory at arrival.

TRANSLATIONAL RELEVANCE: The initial deviation that we observed (despite continuous exposure to the stimulus) suggests the disoriented spatial perception of glaucoma patients which may be relevant to difficulties encountered daily.

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INTRODUCTION: This study aimed to evaluate the value of programmed death-ligand 1 (PD-L1) copy number (CN) alteration as an additional biomarker to standard immunohistochemistry (IHC) in predicting response to immune checkpoint inhibitor (ICI) therapy in advanced NSCLC.

METHODS: Before ICI monotherapy, tumor PD-L1 CN alteration (gain, neutral, or loss) was called using whole-exome sequencing data and compared with IHC results (tumor proportion score ≥50, 1-49, or 0). Progression-free survival (PFS) and overall survival were correlated with both biomarkers. In addition, the impact of CN alteration was further evaluated in two independent cohorts using next-generation sequencing panel.

RESULTS: A total of 291 patients with advanced-stage NSCLC met the study inclusion criteria. Although the IHC classification distinguished the best responsive group (tumor proportion score ≥ 50), the CN-based classification distinguished the worst responsive group (CN loss) from the others (PFS, p = 0.020; overall survival, p = 0.004). After adjusting for IHC results, CN loss was an independent risk factor for progression (adjusted hazard ratio = 1.32, 95% confidence interval: 1.00-1.73, p = 0.049) and death (adjusted hazard ratio = 1.39, 95% confidence interval: 1.05-1.85, p = 0.022). A risk classification system was developed on the basis of IHC and CN profiles, which outperformed the conventional IHC system. In the validation cohorts, CN loss determined by next-generation sequencing panel was independently associated with worse PFS after ICI treatment, revealing its practical value.

CONCLUSIONS: This is the first study to directly compare CN alterations with IHC results and survival outcomes after anti-PD-(L)1 therapy. Tumor PD-L1 CN loss can serve as an adjunct biomarker to predict the lack of response. Prospective studies are required to further validate this biomarker.

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Immune checkpoint inhibitor (ICI) clinically benefits cancer treatment. However, the ICI responses are only achieved in a subset of patients, and the underlying mechanisms of the limited response remain unclear. 160 patients with non-small cell lung cancer treated with anti-programmed cell death protein-1 (anti-PD-1) or anti-programmed death ligand-1 (anti-PD-L1) are analyzed to understand the early determinants of response to ICI. It is observed that high levels of intracellular adhesion molecule-1 (ICAM-1) in tumors and plasma of patients are associated with prolonged survival. Further reverse translational studies using murine syngeneic tumor models reveal that soluble ICAM-1 (sICAM-1) is a key molecule that increases the efficacy of anti-PD-1 via activation of cytotoxic T cells. Moreover, chemokine (CXC motif) ligand 13 (CXCL13) in tumors and plasma is correlated with the level of ICAM-1 and ICI efficacy, suggesting that CXCL13 might be involved in the ICAM-1-mediated anti-tumor pathway. Using sICAM-1 alone and in combination with anti-PD-1 enhances anti-tumor efficacy in anti-PD-1-responsive tumors in murine models. Notably, combinatorial therapy with sICAM-1 and anti-PD-1 converts anti-PD-1-resistant tumors to responsive ones in a preclinical study. These findings provide a new immunotherapeutic strategy for treating cancers using ICAM-1.

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Further optimization of perovskite light-emitting diodes (PeLEDs) is impeded by crystal deformation caused by residual stress and defect formation with subsequent non-radiative recombination. Molecular additives for defect passivation are widely studied; however, the majority have insulating properties that hinder charge injection and transport. Herein, highly efficient green-emitting PeLEDs are reported by introducing semiconducting molecular additives (Fl-OEGA and Fl-C8A). Transmission electron microscopy shows that conjugated additives exist primarily at the grain boundaries of perovskite, and Kelvin probe force microscopy confirms that the variation in contact potential difference between grain boundaries and perovskite crystal domains is significantly reduced. The residual tensile stress is reduced by 13% and the activation energy for ion migration increases in the Fl-OEGA-treated perovskite film, compared to those of the film without additives. Compared to insulating 2,2'-(ethylenedioxy)diethylamine (EDEA), the introduction of semiconducting additives prevents a significant reduction in the charge-transport capability. Furthermore, the PeLEDs with Fl-OEGA show a negligible shift in the turn-on voltage and a significantly smaller decrease in the current density with increasing Fl-OEGA compared to the devices with EDEA. Finally, the 3D CsPbBr3 -PeLEDs show the highest external quantum efficiency of 21.3% by the incorporation of semiconducting Fl-OEGA as a new multifunctional additive.

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Cav3.2 channels play an important role in the afferent nociceptive pathway, which is responsible for both physiological and pathological pain transmission. Cav3.2 channels are upregulated during neuropathic pain or peripheral inflammation in part due to an increased association with the deubiquitinase USP5. In this study, we investigated nine naturally occurring flavonoid derivatives which we tested for their abilities to inhibit transiently expressed Cav3.2 channels and their interactions with USP5. Icariside II (ICA-II), one of the flavonols studied, inhibited the biochemical interactions between USP5 and Cav3.2 and concomitantly and effectively blocked Cav3.2 channels. Molecular docking analysis predicts that ICA-II binds to the cUBP domain and the Cav3.2 interaction region. In addition, ICA-II was predicted to interact with residues in close proximity to the Cav3.2 channel's fenestrations, thus accounting for the observed blocking activity. In mice with inflammatory and neuropathic pain, ICA-II inhibited both phases of the formalin-induced nocifensive responses and abolished thermal hyperalgesia induced by injection of complete Freund's adjuvant (CFA) into the hind paw. Furthermore, ICA-II produced significant and long-lasting thermal anti-hyperalgesia in female mice, whereas Cav3.2 null mice were resistant to the action of ICA-II. Altogether, our data show that ICA-II has analgesic activity via an action on Cav3.2 channels.

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Artemisia is one of the largest genera in the plant family Asteraceae and has long been used in traditional medicine for its antitussive, analgesic, antihypertensive, antitoxic, antiviral, antimalarial, and anti-inflammatory properties. However, the anti-diabetic activity of Artemisia montana has not been broadly studied. The goal of this study was to determine whether extracts of the aerial parts of A. montana and its main constituents inhibit protein tyrosine phosphatase 1B (PTP1B) and α-glucosidase activities. We isolated nine compounds from A. montana including ursonic acid (UNA) and ursolic acid (ULA), which significantly inhibited PTP1B with IC50 values of 11.68 and 8.73 μM, respectively. In addition, UNA showed potent inhibitory activity against α-glucosidase (IC50 = 61.85 μM). Kinetic analysis of PTP1B and α-glucosidase inhibition revealed that UNA was a non-competitive inhibitor of both enzymes. Docking simulations of UNA demonstrated negative binding energies and close proximity to residues in the binding pockets of PTP1B and α-glucosidase. Molecular docking simulations between UNA and human serum albumin (HSA) revealed that UNA binds tightly to all three domains of HSA. Furthermore, UNA significantly inhibited fluorescent AGE formation (IC50 = 4.16 μM) in a glucose-fructose-induced HSA glycation model over the course of four weeks. Additionally, we investigated the molecular mechanisms underlying the anti-diabetic effects of UNA in insulin-resistant C2C12 skeletal muscle cells and discovered that UNA significantly increased glucose uptake and decreased PTP1B expression. Further, UNA increased GLUT-4 expression level by activating the IRS-1/PI3K/Akt/GSK-3 signaling pathway. These findings clearly demonstrate that UNA from A. montana shows great potential for treatment of diabetes and its complications.

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PURPOSE: Brain metastasis is common in patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) at initial presentation. A previous study showed that brain radiotherapy (RT) before first-generation (first-G) EGFR-tyrosine kinase inhibitor (TKI) therapy is associated with longer overall survival than TKI therapy alone. However, there is no data regarding the role of additional brain RT before afatinib therapy.

MATERIALS AND METHODS: Between October 2014 and June 2019, EGFR-mutant NSCLC patients with brain metastases who started first-G EGFR-TKIs (gefitinib or erlotinib) or afatinib as first-line therapy were retrospectively analyzed. This study compared overall survival and intracranial progression-free survival (PFS) between patients who received EGFR-TKIs alone and EGFR-TKIs with brain RT and either a first-G EGFR-TKI or afatinib, respectively.

RESULTS: The median follow-up duration was 29.6 months (range, 1.5 to 116.9 months). In the first-G EGFR-TKI group (n=155), 94 patients (60.6%) received the first-G EGFR-TKI alone and 61 patients (39.4%) received brain RT prior to their first-G EGFR-TKI. In the afatinib group (n=204), 126 patients (61.8%) received afatinib alone and 78 patients (38.2%) received brain RT prior to afatinib. There was no difference in overall survival rates between the groups with RT (35.6 months: 95% confidence interval [CI], 27.9 to 43.3) and without RT (31.4 months: 95% CI, 23.9 to 38.9) in the afatinib group (p=0.58), but there was a significant difference in overall survival in the first-G EGFR-TKI group in a manner favoring additional brain RT (41.1 months: 95% CI, 30.5 to 51.7 vs. 25.8 months: 95% CI, 20.1 to 31.5; p=0.02). Meanwhile, median intracranial PFS was not different between patients who received EGFR-TKI therapy alone vs. EGFR-TKI therapy with brain RT in both the first-G EGFR-TKI (p=0.39) and afatinib (p=0.24) groups.

CONCLUSION: Afatinib therapy alone showed comparable survival outcomes to those of afatinib with brain RT. The current study suggests that brain RT could be an optional, not mandatory, treatment modality when afatinib therapy is considered in patients with EGFR</>-mutant NSCLC.

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PURPOSE: The impact of epidermal growth factor receptor (EGFR) mutation in locally advanced non-small cell lung cancer (NSCLC) remains controversial. This study was conducted to investigate the clinical outcomes and recurrence patterns after definitive chemoradiotherapy (CRT) in patients with unresectable stage III non-squamous-cell lung cancer according to EGFR mutation status.

MATERIALS AND METHODS: We retrospectively reviewed 604 patients with pathologically confirmed stage III NSCLC who were treated with definitive CRT and were examined for EGFR mutation at Samsung Medical Center, Korea, from January 2013 to December 2018. Among them, we identified 236 patients with stage III non-squamous-cell lung cancer who were treated with definitive CRT and were examined for EGFR mutation status. We analyzed the frequency of EGFR mutation, progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and recurrence pattern.

RESULTS: Among 236 patients, EGFR mutation was detected in 71 patients (30.1%) and the median follow-up duration was 41.7 months. There were no significant differences in PFS (9.9 vs. 10.9 months, p=0.236), and ORR to CRT (93.0% vs. 90.3%, p=0.623) according to EGFR mutation status. However, the EGFR mutant group showed significantly higher recurrence (88.7% vs. 75.2%, p=0.022), distant metastasis (76.1% vs. 61.2%, p=0.036) rates, especially brain (38.0% vs. 12.7%, p < 0.001), and better median OS (59.2 vs. 41.3 months, p=0.037) compared with patients without EGFR mutation.

CONCLUSION: Patients with EGFR mutation-positive unresectable stage III non-squamous lung cancer exhibited higher recurrence and distant metastasis rates, especially brain metastasis.

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Morus bombycis has a long history of usage as a treatment for metabolic diseases, especially, diabetes mellitus (DM). Thus, we aimed to isolate and evaluate bioactive constituents derived from M. bombycis leaves for the treatment of DM. According to bioassay-guided isolation by column chromatography, eight compounds were obtained from M. bombycis leaves: two phenolic compounds, p-coumaric acid (1) and chlorogenic acid methyl ester (2), one stilbene, oxyresveratrol (3), two stilbene dimers, macrourin B (4) and austrafuran C (6), one 2-arylbenzofuran, moracin M (5), and two Diels-Alder type adducts, mulberrofuran F (7) and chalcomoracin (8). Among the eight isolated compounds, the anti-DM activity of 3-8 (which possess chemotaxonomic significance in Morus species) was evaluated by inhibition of α-glucosidase, protein tyrosine phosphatase 1B (PTP1B), human recombinant aldose reductase (HRAR), and advanced glycation end-product (AGE) formation as well as by scavenging peroxynitrite (ONOO-), which are crucial therapeutic targets of DM and its complications. Compounds 4 and 6-8 significantly inhibited α-glucosidase, PTP1B, and HRAR enzymes with mixed-type and non-competitive-type inhibition modes. Furthermore, the four compounds had low negative binding energies in both enzymes according to molecular docking simulation, and compounds 3-8 exhibited strong antioxidant capacity by inhibiting AGE formation and ONOO- scavenging. Overall results suggested that the most active stilbene-dimer-type compounds (4 and 6) along with Diels-Alder type adducts (7 and 8) could be promising therapeutic and preventive resources against DM and have the potential to be used as antioxidants, anti-diabetic agents, and anti-diabetic complication agents.

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IMPORTANCE: Over the past 10 years, treatment of non-small cell lung cancer (NSCLC) has been continually revolutionized. However, standard clinical trials may not reflect current multiple lines of treatment and corresponding outcomes in a timely manner.

OBJECTIVE: To investigate outcomes associated with new treatment of NSCLC in a clinical setting.

DESIGN, SETTING, AND PARTICIPANTS: This cohort study included patients with NSCLC between January 1, 2010, and November 30, 2020, who received any anticancer treatment at Samsung Medical Center in Korea. Data were analyzed from November 2021 through February 2022.

EXPOSURES: Clinical and pathological stage, histology, and major druggable sequence variation, including epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), ROS1, RET, MET exon 14 skipping, BRAF V600E, KRAS G12C, and NTRK between 2 periods (period I: 2010-2015 vs period II: 2016-2020).

MAIN OUTCOMES AND MEASURES: The primary outcome was the 3-year survival rate of NSCLC. Secondary outcomes included median overall survival, progression-free survival, and recurrence-free survival.

RESULTS: Among 21 978 patients with NSCLC (median [range] age at diagnosis, 64.1 [57.0-71.0] years; 13 624 males [62.0%]), there were 10 110 patients in period I and 11 868 patients in period II; adenocarcinoma (AD) was the predominant histology (7112 patients [70.3%] in period I and 8813 patients [74.3%] in period II). There were 4224 never smokers [41.8%] in period I and 5292 never smokers [44.6%] in period II. Compared with patients in period I, patients during period II were more likely to undergo molecular tests in the AD (5678 patients [79.8%] vs 8631 patients [97.9%]) and non-AD (1612 of 2998 patients [53.8%] and 2719 of 3055 patients [89.0%]) groups. In patients with AD in period I, 3-year survival rates were 92.8% (95% CI, 91.8%-93.7%), 72.4% (95% CI, 68.3%-76.8%), 56.7% (95% CI, 53.4%-60.2%), and 28.7% (95% CI, 27.0%-30.4%) for stage I, II, III, and IV, respectively. In period II, 3-year survival rates of patients with AD were 95.1% (95% CI, 94.4%-95.9%), 82.5% (95% CI, 79.1%-86.1%), 65.1% (95% CI, 61.8%-68.6%), and 42.4% (95% CI, 40.3%-44.7%) for each stage, respectively. In patients without AD, 3-year survival rates were 72.0% (95% CI, 68.8%-75.3%), 60.0% (95% CI, 56.2%-64.1%), 38.9% (95% CI, 35.6%-42.5%), and 9.7% (95% CI, 7.9%-12.1%) for each stage in period I. In period II, the 3-year survival rates of patients without AD were 79.3% (95% CI, 76.3%-82.4%), 67.3% (95% CI, 62.8%-72.1%), 48.2% (95% CI, 44.5%-52.3%), and 18.1% (95% CI, 15.1%-21.6%) for each stage.

CONCLUSIONS AND RELEVANCE: In this cohort study of 10 years of clinical data, survival outcomes were improved across all stages, with larger increases in patients with stage III to IV disease. The incidence of never-smokers and the use of molecular testing increased.

Abstract

BACKGROUND: The chemokine CXCL13 is known to influence local anti-tumor immunity by recruiting immune cells and forming tertiary lymphoid structures (TLS). It has been hypothesized that TLS, led by the expression of CXCL13, could be a predictive or prognostic biomarker for immunotherapy. We investigated the predictive value of CXCL13 to immune checkpoint inhibitors (ICI) in lung adenocarcinoma.

METHODS: We constructed an exploratory dataset (n = 63) and a validation dataset (n = 57) in metastatic lung adenocarcinoma patients treated with ICI. Based on the clinical response, the difference in gene expression profile, including CXCL13, was evaluated.

RESULTS: From the exploratory dataset, CXCL13 expression was significantly upregulated in the ICI responders (p = 0.002). Survival analysis using a cut-off value of the median expression value of CXCL13 showed prolonged progression-free survival (PFS) (p = 0.004) and overall survival (OS) (p = 0.007). CXCL13 expression was correlated with other immune response genes, such as GZMA, CD8A, IFNG, PRF1, TLS-related gene sets and its receptor, CXCR5. Notably, subgroup analyses based on CXCL13 expression and CD8A showed that CXCL13-upregulated patients demonstrated comparably prolonged survival regardless of CD8A expression. In the validation dataset, CXCL13 upregulation also demonstrated a significant prolongation of both PFS (p = 0.050) and OS (p = 0.026).

CONCLUSION: We observed that CXCL13 upregulation is correlated to better ICI response in lung adenocarcinoma. Our results support that CXCL13 could be an important chemokine in shaping the immunoactive tumor microenvironment which affects the anti-tumor effect of ICI.

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Aglycone- and glycoside-derived forms of flavonoids exist broadly in plants and foods such as fruits, vegetables, and peanuts. However, most studies focus on the bioavailability of flavonoid aglycone rather than its glycosylated form. Kaempferol-3-O-β-d-glucuronate (K3G) is a natural flavonoid glycoside obtained from various plants that have several biological activities, including antioxidant and anti-inflammatory effects. However, the molecular mechanism related to the antioxidant and antineuroinflammatory activity of K3G has not yet been demonstrated. The present study was designed to demonstrate the antioxidant and antineuroinflammatory effect of K3G against lipopolysaccharide (LPS)-stimulated BV2 microglial cells and to evaluate the underlying mechanism. Cell viability was determined by MTT assay. The inhibition rate of reactive oxygen species (ROS) and the production of pro-inflammatory mediators and cytokines were measured by DCF-DA assay, Griess assay, enzyme-linked immunosorbent assay (ELISA), and western blotting. K3G inhibited the LPS-induced release of nitric oxide, interleukin (IL)-6, and tumor necrosis factor-α (TNF-α) as well as the expression of prostaglandin E synthase 2. Additionally, K3G reduced the expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and nuclear factor-kappa B (NF-κB) related proteins. Mechanistic studies found that K3G downregulated phosphorylated mitogen-activated protein kinases (MAPKs) and upregulated the Nrf2/HO-1 signaling cascade. In this study, we demonstrated the effects of K3G on antineuroinflammation by inactivating phosphorylation of MPAKs and on antioxidants by upregulating the Nrf2/HO-1 signaling pathway through decreasing ROS in LPS-stimulated BV2 cells.

Abstract

BACKGROUND: Immune checkpoint inhibitors (ICIs) are an essential treatment for non-small cell lung cancer (NSCLC). Currently, the tumor-related intrinsic factors in response to ICIs have mostly been elucidated in tissue samples. However, tissue immune status and changes in the immune microenvironment can also be reflected and monitored through peripheral blood.

METHODS: Single-cell RNA and T cell receptor (scTCR) sequencing were conducted using peripheral blood mononuclear cells (PBMCs) from 60 patients with stage IV NSCLC. Those samples were prospectively acquired from patients treated with anti-PD(L)-1 therapy for advanced lung cancer. Based on the clinical outcomes, samples were classified as durable clinical benefit (DCB) and non-durable clinical benefit (NCB). The samples constituted paired longitudinal samples, consisting of pre-treatment and on-treatment. Additionally, PBMC samples from 60 healthy donors from the Asian Immune Diversity Atlas project were used as a control.

RESULTS: The dynamic changes in major cell types between pre-treatment and on-treatment PBMCs were associated with an increase in proliferating T cells and NK cells in both DCB and NCB groups. Among T cell subtypes, effector memory CD8+ T cells (CD8+ TEM_GZMK_PDCD1) were increased after ICI treatment in both DCB and NCB. From the lineage trajectory analysis, effector memory CD8+ T cells resided at the bifurcation point, which has the potential to differentiate into lineages with precursor exhausted CD8+ T cells (CD8+ TCM cells) assumed to be related to the ICI response. From the scTCR-seq, effector memory CD8+ T cells along with T cells recognizing unknown antigen expanded and composed of novel clones skewed toward dysfunctional status, especially in on-treatment samples of the DCB group. The extent of immunophenotype conversion capabilities of the TCR with effector memory CD8+ T cells showed remarkable variation in the on-treatment sample in the DCB group.

CONCLUSION: A transitioning T cell subtype identified in PBMCs might be related to the prolonged ICI response. From our study, expansion of effector memory CD8+ T cells with novel TCRs in PBMCs after ICI treatment could contribute to a better clinical outcome in patients with NSCLC. This proof-of-concept research strengthens the use of non-invasive PBMCs in studying systemic changes of immune reactions related to the ICI treatment.

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INTRODUCTION: Thymic epithelial tumors (TETs) are rare but are the most common tumors of the anterior mediastinum. Platinum-based combination chemotherapy is the standard of care for such tumors and is associated with a 50% to 90% objective response rate (ORR) in metastatic disease. Nevertheless, there is no standard chemotherapeutic option after failure of platinum-based combination chemotherapy. Genetic alterations associated with the cell cycle, including pRB, p16INK4A, and cyclin D1, are most often observed in TETs. On the basis of these results, we conducted a phase 2 trial to evaluate the efficacy and safety of palbociclib in patients with recurrent or refractory advanced TETs.

METHODS: This is a phase 2, multicenter, open-label, single-arm study of palbociclib monotherapy in patients with recurrent or metastatic advanced TETs who failed one or more cytotoxic chemotherapies. The patients received 125 mg of oral palbociclib daily for 21 days, followed by a 7-day break. The primary end point was progression-free survival (PFS). The secondary end points were ORR, duration of response, overall survival, and safety.

RESULTS: Between August 2017 and October 2019, a total of 48 patients were enrolled. The median number of previous chemotherapies was one (range: one to four), and 21 (43.7%) of 48 patients received thymectomy. By the WHO classification, the patients were type A (n = 1), type B1 (n = 2), type B2 (n = 8), type B3 (n = 13), thymic carcinoma (n = 23), and unknown (n = 1). With a median follow-up of 14.5 months (range: 0.8-38.2), the median number of cycles of palbociclib monotherapy was 10 (range: 1-40). The ORR was 12.5% (four partial responses in thymoma and two partial responses in thymic carcinoma). The PFS at 6 months was 60.2%, and the median PFS was 11.0 months (95% confidence interval: 4.6-17.4). The median overall survival was 26.4 months (95% confidence interval: 17.4-35.4). The most common treatment-related adverse events of any grade were neutropenia (62.5%), anemia (37.5%), and thrombocytopenia (29.1%), and the most common grade 3/4 treatment-related hematologic adverse event was neutropenia (41.7%). Neutropenia above grade 3 was reversible, and there were no cases with neutropenic fever.

CONCLUSIONS: Palbociclib monotherapy was well tolerated and had encouraging efficacy in patients with TETs who failed platinum-based combination chemotherapy.

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PURPOSE: Associations between immunosenescence and radiation pneumonitis (RP) are largely unknown. We aimed to identify a peripheral blood T cell senescence biomarker to predict RP in patients with non-small cell lung cancer (NSCLC).

METHODS AND MATERIALS: Patients with locally advanced NSCLC who received definitive concurrent chemoradiotherapy (dCRT) were prospectively registered (cohort 1, n=23; cohort 2, n=31). Peripheral blood was collected at baseline, during dCRT, and at 1 month post-dCRT. Patients were dichotomized to grade ≥2 (G2+) RP and grade 0-1 (G0-1) RP. Flow cytometry was performed to assess phenotypes and functional properties of T cell subsets. RP incidence was estimated via competing risk analysis.

RESULTS: Five and six patients exhibited G2+ RP following dCRT in cohorts 1 and 2, respectively. Patients with G2+ RP exhibited a more aged T cell pool and higher frequencies of senescent CD57+CD28-CD8+ T cells than patients with G0-1 RP at baseline, during dCRT, and at 1 month post-dCRT. These senescent cells exhibited increased granzyme B, IFN-γ, and TNF-α production. Higher baseline frequency of CD57+CD28-CD8+ T cells was an independent predictor of G2+ RP (hazard ratio, 8.42; 95% confidence interval, 2.58-27.45; P<0.001). Recursive partitioning analysis revealed three distinct risk groups stratified by baseline CD57+CD28-CD8+ T cell frequency and lung V20 Gy, with 1-year cumulative G2+ RP incidences of 50.0%, 16.7%, and 0% for high-, intermediate-, and low-risk groups, respectively (P=0.002).

CONCLUSIONS: Higher baseline frequencies of CD57+CD28-CD8+ T cells correlated with increased G2+ RP risks. Our results suggest the need for further investigation of the role of T cell senescence on radiation-induced organ damage.

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BACKGROUND: Cholecystokinin (CCK) is one of the most abundant peptides in the central nervous system and is believed to function as a neurotransmitter as well as a gut hormone with an inverse correlation of its level to anxiety and depression. Therefore, CCK receptors (CCKRs) could be a relevant target for novel antidepressant therapy.

METHODS: In silico target prediction was first employed to predict the probability of the bromophenols interacting with key protein targets based on a model trained on known bioactivity data and chemical similarity considerations. Next, we tested the functional effect of natural bromophenols from Symphyocladia latiuscula on the CCK2 receptor followed by a molecular docking simulation to predict interactions between a compound and the binding site of the target protein.

RESULTS: Results of cell-based functional G-protein coupled receptor (GPCR) assays demonstrate that bromophenols 2,3,6-tribromo-4,5-dihydroxybenzyl alcohol (1), 2,3,6-tribromo-4,5-dihydroxybenzyl methyl ether (2), and bis-(2,3,6-tribromo-4,5-dihydroxybenzyl) ether (3) are full CCK2 antagonists. Molecular docking simulation of 1‒3 with CCK2 demonstrated strong binding by means of interaction with prime interacting residues: Arg356, Asn353, Val349, His376, Phe227, and Pro210. Simulation results predicted good binding scores and interactions with prime residues, such as the reference antagonist YM022.

CONCLUSIONS: The results of this study suggest bromophenols 1-3 are CCK2R antagonists that could be novel therapeutic agents for CCK2R-related diseases, especially anxiety and depression.

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Leptomeningeal metastasis (LM) is a rare but fatal clinical condition with a short survival time. The incidence of LM from epidermal growth factor receptor mutant (EGFRm) non-small cell lung cancer (NSCLC) has increased due to the limited efficacy of first- or second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in the central nervous system (CNS). Osimertinib is a third-generation, irreversible, CNS penetrant, oral EGFR TKI that demonstrates promising efficacy in CNS metastases regardless of T790M. Herein, we report four cases of T790M-negative EGFRm NSCLC patients treated with osimertinib combined with systemic chemotherapy, who progressed on prior EGFR TKI and developed LM with extracranial lesions. The combination treatment was well tolerated, and the mean overall survival from LM diagnosis was 14.7 months (95% confidence interval, 10.4 to 19.0). These results suggest that osimertinib combined with systemic chemotherapy would be a reasonable treatment option for T790M-negative EGFRm NSCLC patients who develop LM with extracranial progression to prior EGFR TKI. A further prospective study is warranted.

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Malignant pleural effusion (MPE) is a complication of lung cancer that can be used as an alternative method for tissue sampling because it is generally simple and minimally invasive. Our study evaluated the diagnostic potential of non-small-cell lung carcinoma (NSCLC)-associated MPE in terms of understanding tumor heterogeneity and identifying response factors for EGFR tyrosine kinase inhibitor (TKI) therapy. We performed a single-cell RNA sequencing analysis of 31,743 cells isolated from the MPEs of 9 patients with NSCLC (5 resistant and 4 sensitive to EGFR TKI) with EGFR mutations. Interestingly, lung epithelial precursor-like cells with upregulated GNB2L1 and CAV1 expression were enriched in the EGFR TKI-resistant group. Moreover, GZMK upregulated transitional effector T cells, and plasmacytoid dendritic cells were significantly enriched in the EGFR TKI-resistant patients. Our results suggest that cellular plasticity and immunosuppressive microenvironment in MPEs are potentially associated with the TKI response of patients with EGFR-mutated NSCLC.

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PURPOSE: In early-stage, EGFR mutation-positive (EGFR-M+) non-small cell lung cancer (NSCLC), surgery remains the primary treatment, without personalized adjuvant treatments. We aimed to identify risk factors for recurrence-free survival (RFS) to suggest personalized adjuvant strategies in resected early-stage EGFR-M+ NSCLC.

EXPERIMENTAL DESIGN: From January 2008 to August 2020, a total of 2,340 patients with pathologic stage (pStage) IB-IIIA, non-squamous NSCLC underwent curative surgery. To identify clinicopathologic risk factors, 1,181 patients with pStage IB-IIIA, common EGFR-M+ NSCLC who underwent surgical resection were analyzed. To identify molecular risk factors, comprehensive genomic analysis was conducted in 56 patients with matched case-controls (pStage II and IIIA and type of EGFR mutation).

RESULTS: Median follow-up duration was 38.8 months (0.5-156.2). Among 1,181 patients, pStage IB, II, and IIIA comprised 577 (48.9%), 331 (28.0%), and 273 (23.1%) subjects, respectively. Median RFS was 73.5 months [95% confidence interval (CI), 62.1-84.9], 48.7 months (95% CI, 41.2-56.3), and 22.7 months (95% CI, 19.4-26.0) for pStage IB, II, and IIIA, respectively (P < 0.001). In multivariate analysis of clinicopathologic risk factors, pStage, micropapillary subtype, vascular invasion, and pleural invasion, and pathologic classification by cell of origin (type II pneumocyte-like tumor cell vs. bronchial surface epithelial cell-like tumor cell) were associated with RFS. As molecular risk factors, the non-terminal respiratory unit (non-TRU) of the RNA subtype (HR, 3.49; 95% CI, 1.72-7.09; P < 0.01) and TP53 mutation (HR, 2.50; 95% CI, 1.24-5.04; P = 0.01) were associated with poor RFS independent of pStage II or IIIA. Among the patients with recurrence, progression-free survival of EGFR-tyrosine kinase inhibitor (TKI) in those with the Apolipoprotein B mRNA Editing Catalytic Polypeptide-like (APOBEC) mutation signature was inferior compared with that of patients without this signature (8.6 vs. 28.8 months; HR, 4.16; 95% CI, 1.28-13.46; P = 0.02).

CONCLUSIONS: The low-risk group with TRU subtype and TP53 wild-type without clinicopathologic risk factors might not need adjuvant EGFR-TKIs. In the high-risk group, with non-TRU subtype and/or TP 53 mutation, or clinicopathologic risk factors, a novel adjuvant strategy of EGFR-TKI with others, e.g., chemotherapy or antiangiogenic agents needs to be investigated. Given the poor outcome to EGFR-TKIs after recurrence in patients with the APOBEC mutation signature, an alternative adjuvant strategy might be needed.

Abstract

PURPOSE: Although programmed death 1/programmed death ligand 1 (PD-1/PD-L1) inhibitors are promising agents for recurrent or metastatic nasopharyngeal carcinoma (NPC), PD-1/PD-L1 inhibitor monotherapy has shown modest efficacy. This study evaluated the efficacy and safety of nivolumab plus gemcitabine in patients with NPC who failed prior platinum-based chemotherapy.

PATIENTS AND METHODS: This is a phase II, multicenter, open-label, single-arm study. Patients with recurrent or metastatic NPC received nivolumab 3 mg/kg and gemcitabine 1,250 mg/m2 every 2 weeks until disease progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS). The secondary endpoints included objective response rate (ORR), overall survival (OS), and safety. To identify potential biomarkers, whole-exome sequencing, whole-transcriptome sequencing, and immune phenotype analysis based on Lunit SCOPE IO, an artificial intelligence-powered spatial tumor-infiltrating lymphocyte analyzer, were performed.

RESULTS: Thirty-six patients were enrolled between June 2018 and June 2019. The ORR was 36.1% and disease control rate was 97.2%. With median follow-up of 22.0 months, median PFS was 13.8 months [95% confidence interval (CI), 8.6-16.8 months]. Median OS was not reached, and OS rate at 6 months was 97.0% (95% CI, 80.4%-99.6%). The grade ≥3 treatment-related adverse events were hypertension (2.8%) and anemia (2.8%). In multivariate analysis of mutation of chromatin modifier gene, tumor mutational burden (≥ 2.1 mut/Mb), and somatic copy-number alteration (SCNA) level, the group with high SCNA (> 3 points; HR, 7.0; 95% CI, 1.3-37.9; P = 0.02) had independently associated with poor PFS. Immune phenotype analysis showed that tumors with high proportion of immune-excluded immune phenotype was significantly correlated with poor PFS (HR, 4.4; 95% CI, 1.2-16.2; P = 0.018).

CONCLUSIONS: Nivolumab plus gemcitabine showed promising efficacy with favorable toxicity profiles in patients with advanced NPC in whom platinum-based combination chemotherapy failed.

Abstract

BACKGROUND/OBJECTIVES: Oxidative stress is caused by an imbalance between harmful free radicals and antioxidants. Long-term oxidative stress can lead to an "exhausted" status of antioxidant defense system triggering development of metabolic syndrome and chronic inflammation. Green perilla (Perilla frutescens) is commonly used in Asian cuisines and traditional medicine in southeast Asia. Green perilla possesses numerous beneficial effects including anti-inflammatory and antioxidant functions. To investigate the potentials of green perilla leaf extract (PE) on oxidative stress, we induced oxidative stress by high-fat diet (HFD) in aging mice.

MATERIALS/METHODS: C57BL/6J male mice were fed HFD continuously for 53 weeks. Then, mice were divided into three groups for 12 weeks: a normal diet fed reference group (NDcon), high-fat diet fed group (HDcon), and high-fat diet PE treated group (HDPE, 400 mg/kg of body weight). Biochemical analyses of serum and liver tissues were performed to assess metabolic and inflammatory damage and oxidative status. Hepatic gene expression of oxidative stress and inflammation related enzymes were evaluated by quantitative real-time polymerase chain reaction (qRT-PCR).

RESULTS: PE improved hepatopathology. PE also improved the lipid profiles and antioxidant enzymes, including hepatic glutathione peroxidase (GPx) and superoxide dismutase (SOD) and catalase (CAT) in serum and liver. Hepatic gene expressions of antioxidant and anti-inflammatory related enzymes, such as SOD-1, CAT, interleukin 4 (IL-4) and nuclear factor erythroid 2-related factor (Nrf2) were significantly enhanced by PE. PE also reduced the levels of hydrogen peroxide (H2O2) and malondialdehyde (MDA) in the serum and liver; moreover, PE suppressed hepatic gene expression involved in pro-inflammatory response; Cyclooxygenase-2 (COX-2), nitric oxide synthase (NOS), interleukin 1 beta (IL-1β), and interleukin 6 (IL-6).

CONCLUSIONS: This research opens opportunities for further investigations of PE as a functional food and possible anti-aging agent due to its attenuative effects against oxidative stress, resulting from HFD and aging in the future.

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The purpose of this study was to explore the moderating effect of maladaptive perfectionism on the relationship between cultural sensitivity and counselors-in-training attitudes toward non-dominant sexual identities. A total of 209 counseling graduate students participated in the study. Results showed that cultural sensitivity predicted attitudes toward individuals who identify with a non-dominant sexual identity after controlling for age. Also, a regression analysis demonstrated that maladaptive perfectionism is a moderator in the relationship between cultural sensitivity and attitudes toward individuals who identify with a non-dominant sexual identity among counselors-in-trainings. Implications in the counseling and education field and suggestions for future research are discussed.

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Pueraria lobata leaves contain a variety of phytoestrogens, including flavonoids, isoflavonoids, and coumestan derivatives. In this study, we aimed to identify the active ingredients of P. lobata leaves and to elucidate their function in monoamine oxidase (MAO) activation and Aβ self-aggregation using in vitro and in silico approaches. To the best of our knowledge, this is the first study to elucidate coumestrol as a selective and competitive MAO-A inhibitor. We identified that coumestrol, a coumestan-derivative, exhibited a selective inhibitory effect against MAO-A (IC50 = 1.99 ± 0.68 µM), a key target protein for depression. In a kinetics analysis with 0.5 µg MAO-A, 40-160 µM substrate, and 25 °C reaction conditions, coumestrol acts as a competitive MAO-A inhibitor with an inhibition constant of 1.32 µM. During an in silico molecular docking analysis, coumestrol formed hydrogen bonds with FAD and pi-pi bonds with hydrophobic residues at the active site of the enzyme. Moreover, based on thioflavin-T-based fluorometric assays, we elucidated that coumestrol effectively prevented self-aggregation of amyloid beta (Aβ), which induces an inflammatory response in the central nervous system (CNS) and is a major cause of Alzheimer's disease (AD). Therefore, coumestrol could be used as a CNS drug to prevent diseases such as depression and AD by the inhibition of MAO-A and Aβ self-aggregation.

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Over the years, great attention has been paid to coumarin derivatives, a set of versatile molecules that exhibit a wide variety of biological activities and have few toxic side effects. In this study, we investigated the antidiabetic potential of 6-formyl umbelliferone (6-FU), a novel furanocoumarin isolated from Angelica decursiva. Numerous pharmacological activities of 6-FU have been previously reported; however, the mechanism of its antidiabetic activity is unknown. Therefore, we examined the action of 6-FU on a few candidate-signaling molecules that may underlie its antidiabetic activity, including its inhibition of protein tyrosine phosphatase 1B (PTP1B), α-glucosidase, human recombinant aldose reductase (HRAR), and advanced glycation end-product (AGE) formation (IC50 = 1.13 ± 0.12, 58.36 ± 1.02, 5.11 ± 0.21, and 2.15 ± 0.13 μM, respectively). A kinetic study showed that 6-FU exhibited mixed-type inhibition against α-glucosidase and HRAR and competitive inhibition of PTP1B. Docking simulations of 6-FU demonstrated negative binding energies and close proximity to residues in the binding pockets of those enzymes. We also investigated the molecular mechanisms underlying 6-FU's antidiabetic effects. 6-FU significantly increased glucose uptake and decreased PTP1B expression in insulin-resistant C2C12 skeletal muscle cells. Moreover, 6-FU (0.8-100 μM) remarkably inhibited the formation of fluorescent AGEs in glucose-fructose-induced human serum albumin glycation over the course of 4 weeks. The findings clearly indicate that 6-FU will be useful in the development of multiple target-oriented therapeutic modalities for the treatment of diabetes and diabetes-related complications.

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PURPOSE: A multicenter prospective study to evaluate the feasibility of Physician Orders for Life-Sustaining Treatment (POLST) in oncology practice was conducted between June and December 2017. Factors associated with POLST completion and follow-up outcomes were analyzed.

METHODS: Patients with terminal cancer, aged ≥ 20 years and capable of communicating, were enrolled from seven hospitals. Demographic data were collected and updated in February 2021. Descriptive statistics and logistic regression analyses were conducted.

RESULTS: Among 336 patients, 105 (31.3%) completed POLST, which was more common in male (p = 0.029), patients with better performance (p < 0.001), longer duration of follow-up (p = 0.037), and those living with children (p = 0.023). Male (odds ratio [OR], 2.30; 95% confidence interval [CI], 1.17-3.51; p = 0.012), having good performance status (OR, 2.38; 95% CI, (1.35-4.19); p = 0.003), transferred from other departments (OR, 0.50; 95% CI, (0.26-0.98); p = 0.045), and living with children (OR, 1.94; 95% CI, (1.11-3.47); p = 0.020) were significant predictors of POLST completion. Patients who completed POLST were more likely to enroll in hospice care (p = 0.012) or experience out-of-hospital death (p = 0.016) at end-of-life (EOL). POLST completion showed a strong association with hospice enrollment at EOL (OR, 2.61; 95% CI, (1.08-6.32); p = 0.033).

CONCLUSION: Gender, patient performance, timing of POLST discussion, and type of household were associated with POLST completion. Earlier discussions on POLST could reinforce hospice enrollment or non-aggressive EOL care.

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Retinal angiogenesis was delayed in VSMC-specific Akt1-deficient mice (Akt1∆SMC) but not in Akt2∆SMC mice. The proliferation of ECs, recruitment of pericytes, and coverage of VSMCs to the endothelium were defective in Akt1∆SMC. The silencing of Akt1 in VSMCs led to the downregulation of angiopoietin 1 (Ang1) and the upregulation of Ang2. The activation of Notch3 in VSMCs was significantly reduced in the retinas of Akt1∆SMC mice. Silencing Akt1 suppressed the activation of Notch3. Moreover, the silencing of Notch3 downregulated Ang1, whereas the overexpression of Notch3 intracellular domain (NICD3) enhanced Ang1 expression. The nuclear localization and transcriptional activity of yes-associated protein (YAP) were affected by the expression level of Akt1. Silencing YAP downregulated Ang2 expression, whereas overexpression of YAP showed the opposite results. Ang1 antibody and Ang2 suppressed endothelial sprouting of wild-type aortic tissues, whereas the Ang2 antibody and Ang1 facilitated the endothelial sprouting of aortic tissues from Akt1∆SMC mice. Finally, severe hemorrhage was observed in Akt1∆SMC mice, which was further facilitated under streptozotocin (STZ)-induced diabetic conditions. Therefore, the Akt1-Notch3/YAP-Ang1/2 signaling cascade in VSMCs might play an essential role in the paracrine regulation of endothelial function.

Abstract

BACKGROUND: Patients with ALK-rearranged non-small cell lung cancer (ALK+ NSCLC) inevitably acquire resistance to ALK inhibitors. Longitudinal monitoring of cell-free plasma DNA (cfDNA) next-generation sequencing (NGS) could predict the response and resistance to tyrosine kinase inhibitor (TKI) therapy in ALK+ NSCLC.

METHODS: Patients with ALK+ NSCLC determined by standard tissue testing and planned to undergo TKI therapy were prospectively recruited. Plasma was collected at pretreatment, 2 months-post therapy, and at progression for cfDNA-NGS analysis, Guardant 360.

RESULTS: Among 92 patients enrolled, circulating tumor DNA (ctDNA) was detected in 69 baseline samples (75%): 43 ALK fusions (62.3%) and two ALK mutations without fusion (2.8%). Two patients showed ALK-resistance mutations after ceritinib; G1202R, and co-occurring G1202R and T1151R. Eight patients developed ALK resistance mutations after crizotinib therapy; L1196M (n = 5), G1269A (n = 1), G1202R (n = 1), and co-occurring F1174L, G1202R, and G1269A (n = 1). Absence of ctDNA at baseline was significantly associated with longer progression-free survival (PFS; median 36.1 vs. 11.4 months, p = 0.0049) and overall survival (OS; not reached vs. 29.3 months, p = 0.0200). ctDNA clearance at 2 months (n = 29) was associated with significantly longer PFS (25.4 vs. 11.6 months, p = 0.0012) and OS (not reached vs. 26.1 months, p = 0.0307) than those without clearance (n = 22). Patients with co-occurring TP53 alterations and ALK fusions at baseline (n = 16) showed significantly shorter PFS (7.28 vs. 13.0 months, p = 0.0307) than those without TP53 alterations (n = 25).

CONCLUSIONS: cfDNA-NGS facilitates detection of ALK fusions and resistance mutations, assessment of prognosis, and monitoring dynamic changes of genomic alterations in ALK+ NSCLC treated with ALK-TKI.

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PURPOSE: In acquiring images of the posterior eye, magnetic resonance imaging (MRI) provides low spatial resolution of the overall shape of the eye while optical coherence tomography (OCT) offers high spatial resolution of the limited range. Through the merger of the two devices, we attempted to acquire detailed anatomy of the posterior eye.

METHODS: Optical and display distortions in OCT images were corrected using the Listing reduced eye model. The 3.0T orbital MRI images were placed on the three-dimensional coordinate system of the computer-aided design (CAD) program. Employing anterior scleral canal opening, visual axis, and scleral curvature as references, original and corrected OCT images were ported into the CAD application. The radii of curvature of the choroid-scleral interfaces (Rc values) of all original and corrected OCT images were compared to the MRI images.

RESULTS: Sixty-five eyes of 33 participants (45.58 ± 19.82 years) with a mean Rc of 12.94 ± 1.24 mm on axial MRI and 13.66 ± 2.81 mm on sagittal MRI were included. The uncorrected horizontal OCT (30.51 ± 9.34 mm) and the uncorrected vertical OCT (34.35 ± 18.09 mm) lengths differed significantly from the MRI Rc values (both P < 0.001). However, the mean Rc values of the corrected horizontal (12.50 ± 1.21 mm) and vertical (13.05 ± 1.98 mm) images did not differ significantly from the Rc values of the corresponding MRI planes (P = 0.065 and P = 0.198, respectively).

CONCLUSIONS: Features identifiable only on OCT and features only on MRI were successfully integrated into a unitary posterior eye.

TRANSLATIONAL RELEVANCE: Our CAD-based converging method may establish the collective anatomy of the posterior eye and the neural canal, beyond the range of the OCT.

Abstract

BACKGROUND: Irrespective of the first-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor chosen, acquired resistance to therapy is inevitable. Therefore, a key consideration when assessing therapeutic choices is the availability of subsequent treatment options following disease progression. We assessed clinical outcomes in patients who received first-line afatinib treatment with various second-line treatments including osimertinib for patients acquiring the T790M mutation.

METHODS: A total of 737 EGFR mutation-positive (EGFR M+) non-small cell lung cancer (NSCLC) patients receiving first-line afatinib treatment were categorized by second-line treatment: T790M+ sequentially treated with osimertinib (cohort A, n=116); T790M- given chemotherapy or others (cohort B, n=143); patients with unknown T790M status (cohort C, n=111); and patients who were undergoing afatinib treatment at the time of data collection, were dead, had discontinued afatinib treatment due to serious adverse events or were lost to follow-up (cohort D, n=367). The primary outcomes were total time on treatment (TOT) and TOT for first-line (TOT-1) and second-line treatments (TOT-2). Secondary outcomes were objective response rates (ORR), overall survival (OS), and central nervous system (CNS) efficacy.

RESULTS: Median total TOT in cohorts A, B, C, and D were 35.10 months [95% confidence interval (CI): 30.09-43.53 months], 18.80 months (95% CI: 16.92-20.20 months), 12.00 months (95% CI: 10.22-14.98 months), and 42.60 months (95% CI: 30.95-59.23 months), respectively. The ORR of patients given afatinib was 75.7%. In patients with initial brain metastasis without local treatment, the CNS response rate was 67.0% and CNS progression-free survival was 24.70 months (95% CI: 19.84-33.15 months).

CONCLUSIONS: This study showed that sequential approach of afatinib followed by second line treatment is an effective therapeutic strategy for EGFR M+ NSCLC patients.

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BACKGROUND: The current standard treatment for limited-stage small-cell lung cancer (LS-SCLC) is chemotherapy with concurrent chemoradiotherapy (CCRT).

METHODS: In this single-arm phase II study, patients with LS-SCLC received four cycles of etoposide, cisplatin, and durvalumab every 3 weeks. Thoracic radiotherapy of 52.5 Gy in 25 once-daily fractions was started with the third cycle of chemoimmunotherapy. After CCRT plus durvalumab, patients received durvalumab consolidation therapy every 4 weeks for a maximum of 2 years after study enrolment. Prophylactic cranial irradiation (PCI) was recommended.

RESULTS: Fifty-one patients were enrolled, and 50 were included in the full analysis set. With the median follow-up duration of 26.6 months, the median PFS was 14.4 months (95% confidence interval: 10.3-NA), and the 24-month PFS rate was 42.0%. The median overall survival was not reached with a 24-month overall survival rate of 67.8%. The positive PD-L1 group (n = 22) was not associated with longer PFS (hazard ratio, 0.70; 0.31-1.58) and overall survival (0.64; 0.22-1.84) compared with the negative PD-L1 group (n = 20). Among the 43 patients who were candidates for PCI treatment, the PCI group (n = 22) had significantly fewer events of brain metastasis as the first failure sites compared to the no PCI group (n = 21) (13.6% vs. 42.9%, P = 0.033). There were several grade 3 or 4 adverse events which were well managed with appropriate supportive care.

CONCLUSIONS: Durvalumab with CCRT for LS-SCLC exhibited promising clinical efficacy with a tolerable safety profile, prompting its validation in a randomized study.

TRIAL REGISTRATION: NCT03585998.

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INTRODUCTION: Vascular endothelial growth factor promotes an immunosuppressive tumor microenvironment that can be reverted by an antiangiogenic therapy. This two-stage, phase 2 study aimed to determine the treatment efficacy of adding bevacizumab to atezolizumab in patients with metastatic NSCLC whose disease had progressed after atezolizumab monotherapy.

METHODS: Immune checkpoint inhibitor-naive patients with NSCLC, without EGFR or ALK alterations, whose disease progressed after at least one line of platinum-based chemotherapy were eligible. The patients received atezolizumab 1200 mg once every 3 weeks until radiographic progression (stage I). Then, bevacizumab 15 mg/kg was combined with atezolizumab 1200 mg once every 3 weeks (stage II). The primary end point was the disease control rate (DCR) confined to stage II.

RESULTS: A total of 42 and 24 patients were enrolled in stages I and II, respectively. Most patients had negative programmed death ligand-1 expression (71.4%) and received one or two lines of therapy (95.2%). In stage I, patients achieved a DCR of 35.7% (95% confidence interval [CI]: 21.6-52.0). In stage II, three (12.5%) and 18 (75.0%) of 24 patients had partial response and stable disease, respectively, leading to a DCR of 87.5% (95% CI: 67.6-97.3). For 24 patients enrolled in stage II, the median progression-free survival was 5.6 (95% CI: 4.1-7.1) months and the overall survival was 14.0 (95% CI: 10.7-17.4) months. Treatment-related adverse events occurred in 25% of the patients in stage II, but all were of grade 1 or 2.

CONCLUSIONS: Combination of bevacizumab plus atezolizumab for patients with metastatic NSCLC whose disease had progressed after atezolizumab monotherapy was found to have a promising antitumor activity with good tolerability.

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PURPOSE: Salivary gland cancers (SGCs) are relatively rare but comprise various histologic subtypes, which complicates design of prospective trials. Systemic chemotherapy plays a limited role in treatment of SGCs, but cisplatin and docetaxel showed efficacy in a previous preclinical study. Here, we conduct a prospective, phase II study to evaluate the efficacy and toxicities of cisplatin plus weekly docetaxel in patients with metastatic or recurrent SGC.

MATERIALS AND METHODS: We included patients with histologically confirmed SGCs of the following subtypes: mucoepidermoid carcinoma, adenocarcinoma, ductal carcinoma, or adenoid cystic carcinoma. Patients had no prior systemic chemotherapy for metastatic or recurrent tumors and at least one measurable lesion. Patients were treated with docetaxel 35 mg/m2 (D1, 8) and cisplatin 70 mg/m2 (D1) every 21 days.

RESULTS: Forty-one patients were enrolled between April 2014 and October 2020. The median age was 58 years (range, 32 to 73 years). The most common histologic subtype was adenoid cystic carcinoma (63.4%), followed by ductal carcinoma (24.4%). The most common metastatic site was the lung (75.6%). The median treatment cycle was 5.5 (range, 3 to 8), and the objective response rate was 46.3%, with three complete responses. The median duration of response was 6.8 months (interquartile range, 4.0 to 10.2). The progression-free survival and overall survival were 9.4 months (95% confidence interval [CI], 8.4 to 10.5) and 28.2 months (95% CI, 22.7 to 33.6), respectively. There were no treatment-related deaths. The most common grade 3/4 adverse events were neutropenia (4.9%) and fatigue (4.9%).

CONCLUSION: Cisplatin plus weekly docetaxel is effective and tolerable with manageable toxicity as first-line therapy in patients with metastatic or recurrent SGC.

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Mental stress is on the rise as one of the major health problems in modern society. It is important to detect and manage mental stress to prevent various diseases caused by stress and to maintain a healthy life. The purpose of this paper is to present new heart rate variability (HRV) features based on empirical mode decomposition and to detect acute mental stress through short-term HRV (5 min) and ultra-short-term HRV (under 5 min) analysis. HRV signals were acquired from 74 young police officers using acute stressors, including the Trier Social Stress Test and horror movie viewing, and a total of 26 features, including the proposed IMF energy features and general HRV features, were extracted. A support vector machine (SVM) classification model is used to classify the stress and non-stress states through leave-one-subject-out cross-validation. The classification accuracies of short-term HRV and ultra-short-term HRV analysis are 86.5% and 90.5%, respectively. In the results of ultra-short-term HRV analysis using various time lengths, we suggest the optimal duration to detect mental stress, which can be applied to wearable devices or healthcare systems.

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PURPOSE: Biomarkers on the basis of tumor-infiltrating lymphocytes (TIL) are potentially valuable in predicting the effectiveness of immune checkpoint inhibitors (ICI). However, clinical application remains challenging because of methodologic limitations and laborious process involved in spatial analysis of TIL distribution in whole-slide images (WSI).

METHODS: We have developed an artificial intelligence (AI)-powered WSI analyzer of TIL in the tumor microenvironment that can define three immune phenotypes (IPs): inflamed, immune-excluded, and immune-desert. These IPs were correlated with tumor response to ICI and survival in two independent cohorts of patients with advanced non-small-cell lung cancer (NSCLC).

RESULTS: Inflamed IP correlated with enrichment in local immune cytolytic activity, higher response rate, and prolonged progression-free survival compared with patients with immune-excluded or immune-desert phenotypes. At the WSI level, there was significant positive correlation between tumor proportion score (TPS) as determined by the AI model and control TPS analyzed by pathologists (P < .001). Overall, 44.0% of tumors were inflamed, 37.1% were immune-excluded, and 18.9% were immune-desert. Incidence of inflamed IP in patients with programmed death ligand-1 TPS at < 1%, 1%-49%, and ≥ 50% was 31.7%, 42.5%, and 56.8%, respectively. Median progression-free survival and overall survival were, respectively, 4.1 months and 24.8 months with inflamed IP, 2.2 months and 14.0 months with immune-excluded IP, and 2.4 months and 10.6 months with immune-desert IP.

CONCLUSION: The AI-powered spatial analysis of TIL correlated with tumor response and progression-free survival of ICI in advanced NSCLC. This is potentially a supplementary biomarker to TPS as determined by a pathologist.

Abstract

PURPOSE: Chemoradiotherapy (CRT) followed by consolidation immune checkpoint inhibitors significantly improves survival in unresectable locally advanced non-small cell lung cancer. However, the optimal sequence for CRT and immune checkpoint inhibitors has not yet been established. We investigated the dynamics of peripheral blood immune cells during CRT to determine the best sequence for treatment.

METHODS AND MATERIALS: Peripheral blood samples were prospectively collected pretreatment, weekly during CRT for 6 weeks, and 1 month posttreatment in 24 patients with locally advanced non-small cell lung cancer who received definitive CRT. Immune cell analysis was performed by flow cytometry. Ex vivo PD-1 blockade assays were performed by IFN-γ intracellular cytokine staining.

RESULTS: Lymphopenia was prominently observed during CRT and mostly recovered 1 month post-CRT. Robust proliferation of CD8+ T cells was induced, peaking in the last week during CRT and decreasing post-CRT. The robust proliferation of CD8+ T cells led to an increase in the frequency of CD28-CD57+ replicative senescent and terminally differentiated cells post-CRT. Tumor-reactive CD8+ T cells increased during CRT and peaked in the last week. One month post-CRT, the frequency of tumor-reactive CD8+ T cells decreased and TOXhiTCF1lo terminally exhausted CD8+ T cells significantly increased. Anti-PD-1-induced functional restoration of PD-1+CD8+ T cells was maximized in the last week of CRT and significantly decreased post-CRT.

CONCLUSIONS: The findings suggest that earlier administration of PD-1 blockade may be associated with superior efficacy compared with delayed administration after completion of CRT. These findings provide an immunologic rationale for optimal timing of combining immune checkpoint inhibitors with CRT in clinical trials.

Abstract

PURPOSE: Although programmed cell death 1 (PD-1) or programmed cell death ligand 1 (PD-L1) inhibitors have shown survival benefits in patients with non-small cell lung cancer (NSCLC), most patients progress. This study evaluated whether continuing pembrolizumab with additional chemotherapy after failure of prior PD-1/PD-L1 inhibitor extends survival.

PATIENTS AND METHODS: This placebo-controlled, double-blind, randomized phase II study enrolled patients with NSCLC who received one or two cytotoxic chemotherapy, including at least one platinum-doublet regimen, and progressed on second- or third-line PD-1/PD-L1 inhibitor monotherapy as the last systemic therapy. Patients were randomized (1:1) to pembrolizumab or placebo plus chemotherapy, stratified by histology and clinical outcomes to prior PD-1/PD-L1 inhibitor. The primary endpoint was progression-free survival (PFS).

RESULTS: A total of 98 patients were randomized to the pembrolizumab-chemotherapy (N = 47) and placebo-chemotherapy arm (N = 51). At the median follow-up duration of 10.5 months, there was no statistical difference in PFS [median 4.1 months vs. 5.9 months; HR = 1.06; 95% confidence interval (CI), 0.69-1.62; P = 0.78) and overall survival (median 11.5 months vs. 12.0 months; HR = 1.09; 95% CI, 0.66-1.83; P = 0.73) between the pembrolizumab-chemotherapy and placebo-chemotherapy arms. In a subgroup with PD-L1 expression in ≥50% of tumor cells and favorable clinical outcomes to prior PD-1/PD-L1 inhibitor (partial response or 6 months or longer of stable disease), the pembrolizumab-chemotherapy arm showed a higher 24-month survival rate than the placebo-chemotherapy arm (74% vs. 38%; HR = 0.52; 95% CI, 0.13-2.1; P = 0.34).

CONCLUSIONS: This study did not show a survival benefit with the continuation of pembrolizumab with chemotherapy in patients whose NSCLC progressed on second- or third-line PD-1/PD-L1 inhibitors. See related commentary by Tseng and Gainor, p. 2206.

Abstract

BACKGROUND: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) are standard of care for patients with EGFR mutation-positive non-small-cell lung cancer (NSCLC) with common mutations (Del19 or L858R); however, 7%-23% of NSCLC tumors harbor uncommon EGFR mutations. These mutations are highly heterogeneous, and developments in detection techniques are helping to identify mutations with little or no clinical data.

PATIENTS AND METHODS: In this retrospective, global, multi-center study (NCT04179890), existing health records were identified for consecutive EGFR TKI-naïve patients with uncommon EGFR mutations (T790M, ex20ins, major uncommon [G719X, L861Q, or S768I], or "other" mutations; compound mutations) treated with erlotinib, gefitinib, afatinib, or osimertinib in first or second line. Endpoints included time-to-treatment failure (TTF), objective response rate (ORR), and overall survival (OS).

RESULTS: Overall, 246 patients (median age: 69.5 years; Asian: 84%) were included from 9 countries. Most patients (92%) received an EGFR TKI as first-line therapy; 54%, 43% and 3% received afatinib, first-generation TKIs, and osimertinib, respectively. Median TTF and OS with EGFR TKIs were 9.9 and 24.4 months; ORR was 43%. In patients treated with first-line chemotherapy (n = 20), median TTF and ORR were 6.6 months and 41%. Outcomes were most favorable in patients with major uncommon or compound mutations. Overall, TTF was 11.3 months with afatinib and 8.8 months with first-generation EGFR TKIs across mutation categories. In most mutation categories, median OS was >2 years.

CONCLUSION: In a real-world setting, EGFR TKIs were the preferred treatment option in patients with uncommon EGFR mutations; strongest outcomes were seen in patients with major uncommon and compound mutations.

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OBJECTIVE: The objective of this study was to evaluate the effects of supplementing quercetin extracted from Sophora japonica flower (QS) to the diet of broiler chicks on their growth performance, apparent nutrient digestibility, cecal microbiota, serum lipid profiles, relative organ weight, and breast muscle quality.

METHODS: A total of 1,088 1-day-old broiler chicks (mixed sex) were randomly assigned to four groups based on the initial body weight (43.00±0.29 g). The experimental period was 35 days (starter, days 0 to 7; grower, days 7 to 21; finisher, days 21 to 35). There were 17 replicate cages per treatment and 16 birds per cage. Dietary treatments consisted of birds receiving basal diet without quercetin as the control group and treatment groups consisted of birds fed basal diet supplemented with 0.2, 0.4, or 0.6 g/kg QS.

RESULTS: With the increase of the QS dosage, body weight gain during days 0 to 7 (p = 0.021), 7 to 21 (p = 0.010), and 1 to 35 (p = 0.045), feed intake during days 0 to 7 (p = 0.037) and 1 to 35 (p = 0.025), apparent dry matter digestibility (p = 0.008), apparent energy retention (p = 0.004), cecal lactic acid bacteria counts (p = 0.023), the relative weight of breast muscle (p = 0.014), pH value from breast muscle (p<0.001), and the water holding capacity of breast muscle (p = 0.012) increased linearly, whereas the drip loss from breast muscle (p = 0.001) decreased linearly.

CONCLUSION: The addition of QS in the diet of broiler chicks had positive effects on the breast muscle yield and breast muscle quality, and improved the dry matter digestibility and energy retention by increasing cecal beneficial bacteria counts, thus improving growth performance.

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Previously, we reported the anti-diabetic effect of Morus alba root bark and the compounds therein. In our continuous study of other parts of this plant, the ability of the branch of Morus alba to inhibit α-glucosidase, protein tyrosine phosphatase 1B (PTP1B), and advanced glycation end products (AGEs) formation was evaluated. Moreover, there are no previous studies that have performed enzyme kinetics and molecular docking analyses, along with assessments of peroxynitrite (ONOO-) inhibitory activities. Since the Morus alba branch exhibited favorable inhibitory effects, repeated column chromatography was performed to obtain eight compounds, including four flavonoids (1, 3, 6, 8), one arylbenzofuran (2), one stilbene (5), one Diels-Alder-type adduct (7), and one sterol (4). Among them, compounds 1-3 and 5-7 were mixed-type inhibitors of α-glucosidase, sharing the same catalytic residues with acarbose and the same allosteric sites with (Z)-3-bytylidenephthalide. On the other hand, kuwanon C (1) and oxyresveratrol (5) interacted with residues of the allosteric site (α3 and α6 helices) of PTP1B, indicating their use as non-competitive inhibitors. Interestingly, kuwanon G (7) directly bound the catalytic site, or interrupted the binding between the substrate and the active site, as a mixed-type inhibitor. Moreover, most of the compounds exhibited greater activity against AGE formation and ONOO- than positive controls. The IC50 values required to inhibit ONOO- using compounds 1, 3, 5, 6, and 7 were reported for the first time, and range from 1.08 to 12.92 μM. Based on the structure-activity relationship, the presence of hydroxyl, resorcinol, and prenyl moieties was important in the prevention of diabetes' pathological mechanisms, and these findings have been further supported by molecular docking analysis. These computational and experimental results will be useful in the development of therapeutic candidates to prevent/treat diabetes and its complications.

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INTRODUCTION: Concurrent chemo-radiotherapy (CCRT) with temozolomide (TMZ) is a standard first-line treatment for high-grade glioma. However, if CCRT with TMZ treatment fails, second-line treatment options have limited value. Bevacizumab plus irinotecan is the only available treatment option for such patients. The role of gamma knife radiosurgery (GKS) in patients with high-grade gliomas is not well-established. In this study, we evaluated the efficacy and safety of bevacizumab plus irinotecan with or without GKS in the treatment of high-grade glioma patients who progressed after initially being treated with CCRT with TMZ.

METHODS: We collected clinical data of patients with biopsy-proven high-grade glioma (glioblastoma multiforme (GBM) or anaplastic astrocytoma) who were treated at Samsung Medical Center from January 2015 to December 2020, retrospectively. We evaluated the overall survival (OS), progression-free survival (PFS), and safety of bevacizumab plus irinotecan with or without GKS.

RESULTS: In total, 203 patients were diagnosed with high-grade glioma, including GBM and anaplastic astrocytoma. The median OS was 8.73 months (95% confidence interval [CI]: 7.27-10.18), and the median PFS was 4.36 months (95% CI: 3.75-4.97). Sixty-eight (33.4%) patients underwent GKS prior to bevacizumab plus irinotecan treatment, which led to a significantly prolonged OS (10.13 months, 95% CI: 8.65-11.60 vs. 8.26 months, 95% CI: 7.01-9.51, p = 0.012). The most common adverse events of any grade were neutropenia (36.9%) and thrombocytopenia (22.6%). However, the incidence of adverse events in patients who underwent GKS prior to bevacizumab plus irinotecan was not different compared with those in patients who did not undergo GKS.

CONCLUSIONS: Bevacizumab plus irinotecan was well-tolerated and moderately effective in patients with high-grade gliomas. The addition of GKS prior to bevacizumab plus irinotecan led to a significant OS benefit with a manageable safety profile. GKS prior to bevacizumab plus irinotecan can therefore be considered a potential treatment option for these patients.

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The COVID-19 pandemic has hit face-to-face service fields, including art therapy. The present study examined changes in Korean art therapists' subjective well-being between the pre- and during pandemic periods. We also investigated whether the fear of COVID-19 affected art therapists' subjective well-being and verified the mediating effect of mindfulness on the relationship between COVID-19 fear and subjective well-being. We used the existing data of 203 Korean art therapists' subjective well-being, and recruited 132 new participants. The participants were Korean art therapists and art therapy students who completed a subjective well-being questionnaire, a Fear of COVID-19 scale, and a mindfulness questionnaire. The results indicated lower levels of subjective well-being during the COVID-19 period than pre-pandemic. Furthermore, we confirmed that the fear of COVID-19 lowered subjective well-being, with mindfulness mediating the relationship. This study discusses core components of mindfulness, decentering, and embodiment as attributes shared with art therapy. Our results highlight the importance of dispositional mindfulness to foster subjective well-being during the pandemic.

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π-Conjugated polyelectrolytes (CPEs) have been studied as interlayers on top of a separate hole transport layer (HTL) to improve the wetting, interfacial defect passivation, and crystal growth of perovskites. However, very few CPE-based HTLs have been reported without rational molecular design as ideal HTLs for perovskite solar cells (PeSCs). In this study, the authors synthesize a triphenylamine-based anionic CPE (TPAFS-TMA) as an HTL for p-i-n-type PeSCs. TPAFS-TMA has appropriate frontier molecular orbital (FMO) levels similar to those of the commonly used poly(bis(4-phenyl)-2,4,6-trimethylphenylamine) (PTAA) HTL. The ionic and semiconducting TPAFS-TMA shows high compatibility, high transmittance, appropriate FMO energy levels for hole extraction and electron blocking, as well as defect passivating properties, which are confirmed using various optical and electrical analyses. Thus, the PeSC with the TPAFS-TMA HTL exhibits the best power conversion efficiency (PCE) of 20.86%, which is better than that of the PTAA-based device (PCE of 19.97%). In addition, it exhibits negligible device-to-device variations in its photovoltaic performance, contrary to the device with PTAA. Finally, a large-area PeSC (1 cm2 ) and mini-module (3 cm2 ), showing PCEs of 19.46% and 18.41%, respectively, are successfully fabricated. The newly synthesized TPAFS-TMA may suggest its great potential as an HTL for large-area PeSCs.

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INTRODUCTION: This study set out to quantitatively examine the relationship between personality and color, focusing on connotations and preference.

METHOD: A total of 854 Koreans, aged from 20 to 60, participated in the study. They indicated which colors they associated with various personality words, completed the Ten Item Personality Inventory, and ranked their color preferences. We analyzed the data using frequency analysis, correlation analysis, t-tests, regression analysis, and cluster analysis.

RESULTS: The analyses revealed that all five personality types have characteristic color associations. Through regression analysis, we found that color preference can significantly predict personality. The comparison among personality groups produced by cluster analysis confirmed that people with strong specific personalities prefer the colors that symbolize their personalities.

DISCUSSION: This study's findings highlight the relationship between personality and color preference. The limitations and suggestions for future studies are also presented.

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PURPOSE: We evaluated baseline 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) metabolic parameters for predicting prognosis in patients with head and neck squamous cell carcinoma (HNSCC) who were receiving immune checkpoint inhibitors (ICIs). In addition, we also investigated the relationships between immunohistochemical (IHC) biomarkers and metabolic parameters.

MATERIALS AND METHODS: A total of 39 patients with HNSCC who underwent 18F-FDG PET/CT prior to ICI therapy between November 2015 and December 2020 were enrolled. PET parameters of tumor lesions included standardized uptake values, metabolic tumor volume (MTV), total lesion glycolysis (TLG), and spleen-to-liver ratio (SLR). Clinical variables, IHC markers, and derived neutrophil-to-lymphocyte ratio (dNLR) were also obtained. Analysis was performed using Cox proportional hazard model, Kaplan-Meier method with log-rank test, and Spearman's correlation.

RESULTS: Total MTV (TMTV), total TLG (TTLG), and a combined parameter consisting of TMTV and dNLR were significant predictors for progression-free survival (PFS) in univariable analysis (TMTV, p = 0.018; TTLG, p = 0.027; combined parameter, p = 0.021). Above all, the combined parameter was an independent prognostic factor for PFS in multivariable analysis. The group with low TMTV and low dNLR had longer PFS than the group with high TMTV and high dNLR (p = 0.036). SLR was the only significant predictor for overall survival (p = 0.019). Additionally, there was a negative correlation between programmed cell death-ligand 1 expression (one of the IHC markers) and MTV in subgroup analysis.

CONCLUSION: PET parameters on baseline 18F-FDG PET/CT were predictive biomarkers for prognosis in patients with HNSCC undergoing ICI therapy. With dNLR, more accurate prognostic prediction could be possible.

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BACKGROUND: Oropharyngeal squamous cell carcinoma (OPSCC) is the most common neoplasm originating at the base of the tongue or in the tonsils or soft palate. In this study, we investigated the prognostic value of FOXP3+ regulatory T cells in OPSCC.

METHODS: Tumor tissues of patients with locally advanced OPSCC were analyzed using quantitative multiplex immunohistochemistry. Staining of CD8+ T cells, conventional CD4+FOXP3- T cells (Tconv cells), CD4+FOXP3+ regulatory T cells (Treg cells), CD20+ B cells, and CD68+ macrophages was performed, and cell density was evaluated in both the tumor and its stroma.

RESULTS: Among the 71 patients included in this study, males constituted 93.0% of the cohort, and the median age was 59 years (range: 42-80 years). A total of 56 patients (78.9%) had a smoking history, and 53 (74.6%) patients were positive for human papillomavirus (HPV). The most frequent site of OPSCC was the tonsils (70.4%), followed by the base of the tongue (25.4%). The proportion of Treg cells was lower in the tumors of patients with HPV than in those of patients without HPV. Patients with OPSCC whose tumor Treg cell levels were above the median had longer relapse-free survival (RFS) periods than those with tumor Treg cell levels below the median (HR, 0.12; 95% CI, 0.03-0.46; p = 0.02). Our multivariate analysis identified high Treg levels (HR, 0.13; 95% CI, 0.02-1.00; p = 0.05) as an RFS factor that predicted a good prognosis.

CONCLUSIONS: Our results demonstrated that high Treg cell density in locally advanced OPSCC tumors was correlated with longer RFS.

Abstract

OBJECTIVE: Two recent non-interventional trials, GioTag and UpSwinG, demonstrated encouraging time-to-treatment failure (TTF) and overall survival (OS) in patients with epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC) (Del19 or L858R) who received sequential afatinib/osimertinib, especially in Asians. Here, we have undertaken a combined analysis of Asian patients from both studies.

MATERIALS AND METHODS: Existing medical/electronic records were identified for consecutive EGFR-tyrosine kinase inhibitor (TKI)-naïve patients who received first-line afatinib/second-line osimertinib in "real-world" practice (all T790M-positive). Patients with active brain metastases were excluded. The primary objective was TTF. OS was a key secondary objective.

RESULTS: One hundred and sixty-eight patients were analyzed. Most patients were recruited from South Korea or Japan (52/21%). At the start of afatinib, median age (range) was 61.5 years (35-88), 58% were female, Eastern Cooperative Oncology Group Performance Status (ECOG PS) (0/1/≥2) was 29/62/9%, 17% had brain metastases, and EGFR mutation status (Del19/L858R) was 65/35%. At the start of osimertinib, ECOG PS (0/1/≥2) was 22/61/17% and 14% had brain metastases. Median TTF and OS were 30.0 months (95% CI: 24.5-32.5) and 45.2 months (95% CI: 41.7-71.1), respectively. Median OS was 63.5 months in patients with a Del19 mutation. Median OS in patients with brain metastases or ECOG PS ≥2 was 26.4 and 33.1 months, respectively.

CONCLUSION: Sequential afatinib/osimertinib showed encouraging activity in Asian patients with EGFR mutation-positive NSCLC and T790M-mediated acquired resistance, especially those with Del19-positive disease. Activity was observed across "real-world" patients including those with poor ECOG PS and/or brain metastases. ECOG PS and incidence of brain metastases remained stable prior to, and after, afatinib.

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The current study investigated the mediation effect of self-focused attention on the relationship between South Korean novice counselors' perfectionism and psychological burnout. We also examined whether cognitive emotion regulation strategies moderated the mediation effect of self-focused attention with a sample of 208 South Korean novice counselors. Moderated mediation was tested with the PROCESS 2.16.3 macro for SPSS and the index of moderated mediation. Bootstrapping analyses were used to examine the mediation effect of self-focus on the relationship between perfectionism and psychological burnout. A hierarchical multiple regression analysis was also conducted to examine the moderation of emotion regulation strategies. Findings indicate that self-focused attention partially mediated the relationship between perfectionism and psychological burnout. Moreover, the indirect effect of perfectionism on psychological burnout through self-focused attention varied depending on levels of adaptive emotion regulation strategies. We present implications for counseling and suggestions for future research in an international context.

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PURPOSE: Metachronous brain-only oligorecurrence in patients with non-small cell lung cancer (NSCLC) is a rare event with favorable prognosis, but the clinical outcome has not been fully determined. We retrospectively analyzed clinical outcomes and prognostic factors in metachronous brain-only oligorecurrence in patients with NSCLC who underwent definitive treatment.

MATERIALS AND METHODS: We reviewed 4,437 NSCLC patients without oncogenic driver mutations who underwent definitive treatment between 2008 and 2018. Among them, we identified 327 patients who developed 1 to 5 brain metastases with or without systemic metastasis. Of the 327 patients, 71 had metachronous brain-only oligorecurrence without extracranial progression and were treated with local therapy to the brain. Overall survival (OS), progression-free survival (PFS), and prognostic factors affecting OS were analyzed.

RESULTS: The median OS was 38.9 months (95% confidence interval [CI], 21.8 to 56.1 months) in 71 patients. The 2-year OS rate was 67.8% and the 5-year OS rate was 33.1%. The median PFS was 25.5 months (95% CI, 12.2 to 14.4 months). The longest surviving patient had a survival period of 115 months. Through multivariate analysis, Eastern Cooperative Oncology Group ≥ 1 (hazard ratio, 5.33; p=0.005) was associated with poor survival. There was no significant difference in OS between patients with local therapy and those with local plus systemic therapy (18.5 months vs. 34.7 months, p=0.815).

CONCLUSION: Metachronous brain-only oligorecurrence NSCLC patients who underwent definitive treatment experienced long-term survival with local therapy, highlighting the unique patient population. The role of systemic chemotherapy in this patient population requires further investigation.

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In this study, we demonstrated two deep-blue TADF emitters, BO-tCzPhICz and BO-tCzDICz, for solution-processable thermally activated delayed fluorescence organic light-emitting diodes (TADF-OLEDs). They were synthesized by employing an organoboron acceptor and 9-(3,6-di-tert-butyl-9H-carbazol-9-yl)-5-phenyl-5,12-dihydroindolo[3,2-a]carbazole (tCzPhICz) and 12-(3,6-di-tert-butyl-9H-carbazol-9-yl)-15H-diindolo[2,3-b:1',2',3'-lm]carbazole (tCzDICz) as bulky aryl-annulated [3,2-a] carbazole donors, respectively. Both emitters showed sufficient solubility in organic solvents, narrow deep-blue emission, and small energy difference (ΔEST) between singlet and triplet states, which can be applied to solution-processable deep-blue TADF-OLEDs. Solution-processed OLEDs exploiting these TADF emitters displayed deep-blue electroluminescence with CIEy <0.1, and high external quantum efficiencies of 17.8 and 14.8% were observed for BO-tCzPhICz and BO-tCzDICz, respectively. The emitter bearing bulky ICz-based donating units shows highly promising potential for high-efficiency solution-processable deep-blue TADF-OLEDs.

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Alterations in the expression and/or activity of brain G-protein-coupled receptors (GPCRs) such as dopamine D1R, D2LR, D3R, and D4R, vasopressin V1AR, and serotonin 5-HT1AR are noted in various neurodegenerative diseases (NDDs). Since studies have indicated that flavonoids can target brain GPCRs and provide neuroprotection via inhibition of monoamine oxidases (hMAOs), our study explored the functional role of kurarinone, an abundant lavandulated flavonoid in Sophora flavescens, on dopamine receptor subtypes, V1AR, 5-HT1AR, and hMAOs. Radioligand binding assays revealed considerable binding of kurarinone on D1R, D2LR, and D4R. Functional GPCR assays unfolded the compound's antagonist behavior on D1R (IC50 42.1 ± 0.35 μM) and agonist effect on D2LR and D4R (EC50 22.4 ± 3.46 and 71.3 ± 4.94 μM, respectively). Kurarinone was found to inhibit hMAO isoenzymes in a modest and nonspecific manner. Molecular docking displayed low binding energies during the intermolecular interactions of kurarinone with the key residues of the deep orthosteric binding pocket and the extracellular loops of D1R, D2LR, and D4R, validating substantial binding affinities to these prime targets. With appreciable D2LR and D4R agonism and D1R antagonism, kurarinone might be a potential compound that can alleviate clinical symptoms of Parkinson's disease and other NDDs.

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In the present study, we investigated the structure-activity relationship of naturally occurring hesperetin derivatives, as well as the effects of their glycosylation on the inhibition of diabetes-related enzyme systems, protein tyrosine phosphatase 1B (PTP1B) and α-glycosidase. Among the tested hesperetin derivatives, hesperetin 5-O-glucoside, a single-glucose-containing flavanone glycoside, significantly inhibited PTP1B with an IC50 value of 37.14 ± 0.07 µM. Hesperetin, which lacks a sugar molecule, was the weakest inhibitor compared to the reference compound, ursolic acid (IC50 = 9.65 ± 0.01 µM). The most active flavanone hesperetin 5-O-glucoside suggested that the position of a sugar moiety at the C-5-position influences the PTP1B inhibition. It was observed that the ability to inhibit PTP1B is dependent on the nature, position, and number of sugar moieties in the flavonoid structure, as well as conjugation. In the kinetic study of PTP1B enzyme inhibition, hesperetin 5-O-glucoside led to mixed-type inhibition. Molecular docking studies revealed that hesperetin 5-O-glucoside had a higher binding affinity with key amino residues, suggesting that this molecule best fits the PTP1B allosteric site cavity. The data reported here support hesperetin 5-O-glucoside as a hit for the design of more potent and selective inhibitors against PTP1B in the search for a new anti-diabetic treatment.

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Isoliquiritigenin (= 4,2',4'-Trihydroxychalcone) (ILG) is a major constituent of the Glycyrrhizae Rhizoma that has significant neuroprotective functions. In the present study, we re-examined the potential of ILG to inhibit human monoamine oxidase (hMAO) in vitro and established its mechanism of inhibition through a kinetics study and molecular docking examination. ILG showed competitive inhibition of hMAO-A and mixed inhibition of hMAO-B with IC50 values of 0.68 and 0.33 µM, respectively, which varied slightly from the reported IC50 values. Since ILG has been reported to reduce dopaminergic neurodegeneration and psychostimulant-induced toxicity (both of which are related to dopamine and vasopressin receptors), we investigated the binding affinity and modulatory functions of ILG on dopamine and vasopressin receptors. ILG was explored as an antagonist of the D1 receptor and an agonist of the D3 and V1A receptors with good potency. An in silico docking investigation revealed that ILG can interact with active site residues at target receptors with low binding energies. These activities of ILG on hMAO and brain receptors suggest the potential role of the compound to ameliorate dopaminergic deficits, depression, anxiety, and associated symptoms in Parkinson's disease and other neuronal disorders.

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BACKGROUND: Pralsetinib, an RET inhibitor, has shown a dramatic response in patients with RET fusion- or mutation-positive tumours in previous studies. As a novel target agent, however, the safety of pralsetinib remains to be determined. Herein, we present two cases of extrapulmonary tuberculosis (TB) that developed during pralsetinib therapy.

METHODS: From April 2020, we administered pralsetinib to a total of 10 patients with RET fusion-positive non-small cell lung cancer under the compassionate use program. We retrospectively analysed the clinical efficacy of and adverse events related to pralsetinib therapy.

RESULTS: Of the nine patients with measurable lesions, seven achieved a partial response. Additionally, one patient without measurable lesions also showed a clinical response. As of January 8, 2021, nine patients were still receiving pralsetinib therapy, while only one had discontinued pralsetinib therapy. Most adverse events were mild and manageable. However, two patients experienced extrapulmonary TB shortly after starting pralsetinib. The disease was well controlled with anti-TB medication, and the cancer lesions were managed through ongoing pralsetinib therapy.

CONCLUSION: The development of TB during pralsetinib therapy is worth noting, although further large studies are required to demonstrate definitive relationship between causality and underlying mechanism.

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BACKGROUND: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are standard of care for EGFR mutation-positive non-small cell lung cancer (NSCLC). However, optimal sequence of treatment has yet to be defined. Overall survival (OS) is influenced by the availability/use of subsequent therapy after first-line treatment. Emergence of T790M is the main mechanism of resistance to afatinib and second-line osimertinib could be a treatment option in this instance.

METHODS: In this non-interventional, global study (NCT04179890), existing medical/electronic records were identified for consecutive EGFR TKI-naïve patients with EGFR mutation-positive NSCLC (Del19 or L858R) treated with first-line afatinib and second-line osimertinib in regular clinical practice (n = 191; all T790M-positive). The primary objective was time to treatment failure (TTF). Key secondary objectives were OS and objective response rate (ORR).

RESULTS: At the start of afatinib treatment, median age (range) was 62 years (34-88). Fifty-five percent of patients were female and 67% were Asian. ECOG PS (0/1/≥2) was 31%/57%/12%. Fourteen percent of patients had brain metastases. At the start of osimertinib treatment, ECOG PS (0/1/≥2) was 25%/61%/14% and 14% had brain metastases (rising to 29% at the end of osimertinib treatment). The source of biopsy material (solid/liquid) was 86%/3% at the start of afatinib and 54%/33% at start of osimertinib. Mutations were mainly detected with PCR methods. Overall, median TTF was 27.7 months (95% CI: 24.0-30.2) and median OS was 36.5 months (95% CI: 32.9-41.8). ORR with afatinib and osimertinib was 74% and 45%. TTF, OS and ORR were generally consistent across subgroups.

CONCLUSION: Sequential afatinib and osimertinib demonstrated encouraging activity in patients with EGFR mutation-positive NSCLC and acquired T790M. Activity was observed across all subgroups, including patients with poor ECOG PS or brain metastases. ECOG PS and incidence of brain metastases remained stable prior to, and after, afatinib treatment.

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BACKGROUND: A certain proportion of non-small cell lung cancer (NSCLC) with activating EGFR mutations showed resistance to tyrosine kinase inhibitors (TKIs) by transforming their histology into small cell lung cancer (SCLC). In this study, we evaluated the molecular characteristics of transformed SCLCs.

METHODS: Eighteen SCLC tissue samples transformed after EGFR TKI treatment were used for the analysis. Immunohistochemistry was conducted to evaluate the molecular subtype using antibodies representative of the major transcriptional factor-based molecular subtypes, ASCL1 (SCLC-A), NEUROD1 (SCLC-N), POU2F3 (SCLC-P), and YAP1. Subtypes were categorized based on a predefined criteria.

RESULTS: Among the study population (n=18), most of the patients were initially diagnosed with adenocarcinoma (n=17), and one patient was diagnosed with adenosquamous histology. Eight patients (44.4%) were never-smokers, and nine patients were women (50.0%). Staining of pre-transformation sample was conducted in six patients, and five of them showed no discernible expression for ASCL1, NEUROD1, or POU2F3. However, the proportion of molecular subtypes after SCLC transformation was predominantly SCLC-N (n=9, 50.0%), followed by SCLC-Triple Negative (SCLC-TN; n=5, 27.8%) and SCLC-A (n=4, 22.2%). The median overall survival from TKI initiation was longer in patients who transformed to SCLC-A (P=0.009) than in those who transformed to either SCLC-N or SCLC-TN. However, the overall survival difference since SCLC transformation was not significant (P=0.370).

CONCLUSIONS: In our series, SCLC-N subtype was prevalent in SCLC transformed after EGFR TKI treatment. In addition, overall survival and the time to SCLC transformation from the EGFR TKI treatment were longer in patients who transformed to the SCLC-A type. Large-scale data will be required to confirm our findings.

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Three V-shaped host molecules with a cyclohexane linker were successfully synthesized for thermally activated delayed fluorescence organic light-emitting diodes (TADF-OLEDs). The unipolar host molecules, BBCzC and BTDC, contained two 9-phenyl-9H-3,9'-bicarbazole (PBCz) moieties and two 2,12-di-tert-butyl-7-phenyl-5,9-dioxa-13b-boranaphtho[3,2,1-de]anthracene (PDBNA) moieties, respectively. BCzTC, a bipolar host molecule, consisted of a donor unit, PBCz, and an acceptor unit, PDBNA, connected by a cyclohexane linker. Three host molecules showed good solubility in various organic solvents, making them suitable for solution processing. Among the solution-processed green TADF-OLEDs using three host molecules and a green TADF emitter, the one with BCzTC showed the highest external quantum efficiency of up to 30% with a high power efficiency of 71 lm W-1 and a current efficiency of 102 cd A-1. Compared with BBCzC and BTDC, BCzTC exhibited a relatively high photoluminescence quantum yield (PLQY), an excellent balance in hole and electron transport properties in the emitting layer, and more efficient energy transfer to the emitter, giving such an excellent device performance.

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BACKGROUND: The American Society for Clinical Oncology recently launched the minimal common oncology data elements project to facilitate cancer data interoperability. However, clinical data are often unrecorded in an organized way, and converting them into a structured format can be time-consuming. Clinical Data Warehouse (CDW) is a database that consolidates data from different clinical sources. However, the clinical data extracted from this database include not only structured data but also natural language generated during clinical practice. Therefore, applying these data to a clinical study is challenging because they are unstructured, and unformatted to allow essential content to be found. This study determined how best to organize a huge amount of clinical data to evaluate the upper aerodigestive tract cancers' clinical features and outcomes, including cancer of the head and neck, esophagus, lung, thymus, and mesothelioma.

METHODS: The Real-time autOmatically updated data warehOuse in healThcare (ROOT) uses six main regions to describe the journey of cancer patients. This study, developed an algorithm optimized for each disease category using natural language processing of unstructured data and data capture of structured data. Data from patients diagnosed at the Samsung Medical Center from 2008-2020 were used.

RESULTS: Comprehensive clinical data for 67,617 patients across six tumor types: 28,954 with non-small-cell lung cancer, 2,540 with small-cell lung cancer, 30,035 with head and neck cancer, 4,950 with esophageal cancer, 966 with thymic cancer, and 172 with mesothelioma were collected. Additionally, the results of a longitudinal molecular study, including epidermal growth factor receptor (EGFR) mutations, anaplastic lymphoma kinase (ALK) tests, and next-generation sequencing (NGS), were included. Scattered information was integrated and automatically built up to match the cohort, allowing users to capture the most updated test results and treatment outcomes.

CONCLUSIONS: This landmark study documented the successful construction of a real-time updating system for medical big data, based on the CDW program.

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