Efficacy of epidermal growth factor in suppressing inflammation and proliferation in pterygial fibroblasts through interactions with microenvironmental M1 macrophages.

The protein epidermal growth factor (EGF), which plays a crucial role in promoting cell proliferation and survival, has recently demonstrated potential in reducing inflammation. In this study, we examined the impact of EGF on the anti-inflammatory and anti-proliferative properties of pterygium, a prevalent hypervascular proliferative disease affecting the ocular surface. In surgically excised tissues, markers for fibrotic and inflammatory signals, including VIM, ACTA2, FAP, MMP2, VCAM1, ICAM1, CD86, IL6, and IL1B were upregulated in the pterygium body stroma compared to the normal conjunctival stroma. EGF exerted anti-inflammatory and anti-vasculogenic effects on pterygial fibroblasts when co-cultured with M1 macrophages. Moreover, exosomes derived from EGF-preconditioned M1 macrophages suppressed the heightened inflammatory and vasculogenic signals in pterygial fibroblasts induced by exosomes from M1 macrophages. Paradoxically, the proliferation of pterygial fibroblasts was inhibited by EGF in the in vitro microenvironment with M1 macrophages, despite EGF being known as a growth factor. EGF-preconditioning of M1 macrophages rescued the increased proliferation of pterygial fibroblasts induced by exosomes from M1 macrophages. In conclusion, our findings demonstrate that EGF effectively mitigates inflammation and proliferation in pterygial fibroblasts within a microenvironment containing M1 macrophages.

Distinct activation of M1 and M2 macrophages in the primary pterygium lymphangiogenesis.

The precise role and innate immunological mechanisms underlying lymphangiogenesis in pterygium remain unclear. This study aimed to investigate the presence of M1 and M2 macrophages and their correlation with pro-lymphangiogenic activation and lymphatic endothelial expression in human pterygium stromal tissues. We analyzed human pterygium and subject-matched normal conjunctival tissues for the expression of these factors and conducted in vitro experiments to assess interactions between macrophages and pterygium fibroblasts. Myeloid and M1 macrophage markers were upregulated in pterygium. M1 macrophages were associated with the upregulation of pro-lymphangiogenic vascular endothelial growth factor C (Vegfc) in pterygium tissues and induced inflammatory signals in pterygium fibroblasts. In contrast, lymphatic vessel endothelial hyaluronan receptor 1 (Lyve1) expression was associated with M2 markers but not with M1 markers. Notably, the clinical severity of pterygium was inversely correlated with the expression of the M2 marker Cd163. These findings suggest that M1 and M2 macrophages play distinct roles in the pathogenesis of pterygium, with M1 macrophages enhancing lymphangiogenic stimulation and inflammatory responses, while M2 macrophages are associated with Lyve1 expression and reduced severity of pterygium. Understanding these mechanisms may advance our current understanding of lymphatic biology in pterygium.

KEAP1-NRF2 pathway as a novel therapeutic target for EGFR-mutant non-small cell lung cancer.

BACKGROUND: Kelch-like ECH-associated protein 1 (KEAP1)-nuclear factor erythroid-2-related factor 2 (NRF2) pathway is a major regulator protecting cells from oxidative and metabolic stress. Studies have revealed that this pathway is involved in mediating resistance to cytotoxic chemotherapy and immunotherapy, however, its implications in oncogene-addicted tumors are largely unknown. This study aimed to elucidate whether this pathway could be a potential therapeutic target for epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer. METHODS: We measured the baseline expression of NRF2 using EGFR-mutant parental cells and acquired gefitinib resistant cells. We investigated whether NRF2 inhibition affected cell death in vitro and tumor growth in vivo using a xenograft mouse model, and compared the transcriptional changes before and after NRF2 inhibition. RESULTS: Baseline NRF2 expression was enhanced in PC9 and PC9 with gefitinib resistance (PC9/GR) cells than in other cell lines, with a more prominent expression in PC9/GR. The NRF2 inhibitor induced NRF2 downregulation and cell death in a dose-dependent manner. Co-treatment with an NRF2 inhibitor enhanced osimertinib-induced cell death in vitro, and potentiated tumor growth inhibition in a PC9/GR xenograft model. Finally, RNA sequencing revealed that NRF2 inhibition resulted in the altered expression of multiple genes involved in various signaling pathways. CONCLUSION: We identified that NRF2 inhibition enhanced cell death and inhibited tumor growth in TKI-resistant lung cancer with EGFR-mutation. Thus, NRF2 modulation may be a novel therapeutic strategy to overcome the resistance to EGFR-tyrosine kinase inhibitors.

Prognostic Impact of Reactive Oxygen Species Modulator 1 in Surgically Resected Epidermal Growth Factor Receptor-Mutant Lung Adenocarcinomas.

INTRODUCTION: Reactive oxygen species modulator 1 (Romo1) is a novel protein that is critically involved in the intracellular production of reactive oxygen species. Evidence has revealed that Romo1 is associated with treatment outcomes of various human malignancies, including lung cancer. However, the clinical implications of this protein in surgically resected lung cancers harboring epidermal growth factor receptor (EGFR) mutations have not been investigated. METHODS: Data were collected from patients who underwent curative resection of EGFR-mutant lung adenocarcinoma. Romo1 protein expression levels were measured in the tumor tissue using immunohistochemical staining and evaluated semi-quantitatively using the histochemical score. Univariate and multivariate analyses were performed to identify the clinicopathological parameters that may be associated with clinical outcomes. RESULTS: A total of 98 samples were analyzed. Using the cutoff H score of 200, the population was classified into low (n = 73) and high (n = 25) Romo1 groups. Romo1 expression was significantly higher in smokers, patients with stage III disease, and patients who experienced recurrence after surgery (all p < 0.05). Multivariate analyses showed that advanced-stage and poorly differentiated cancers were associated with shorter disease-free survival (DFS). In addition, high Romo1 expression was independently associated with poor DFS (hazard ratio = 2.18, 95% confidence interval: 1.10-4.32, p = 0.0261). CONCLUSIONS: Our data showed that Romo1 overexpression was significantly associated with early recurrence in patients with resected EGFR-mutant lung adenocarcinoma. Although large-scale studies are required, Romo1 may play a prognostic role in this patient population.

Clinical significance of the advanced lung cancer inflammation index in patients with limited-stage small cell lung cancer treated with chemoradiotherapy.

The aim of the study was to investigate the prognostic significance of the advanced lung cancer inflammation index (ALI) in patients with limited-stage small-cell lung cancer (LS-SCLC) undergoing definite chemo-radiotherapy (CRT). We included 87 patients with LS-SCLC from South Korea, treated between 2005 and 2019 with definite CRT. ALI was calculated using body mass index, serum albumin, and neutrophil-lymphocyte ratio. We categorized 38 patients into the high ALI group (ALI ≥ 44.3) and 48 into the low ALI group (ALI < 44.3). Patients in the high ALI group exhibited longer overall survival (OS) than patients in the low ALI group. In multivariate analysis, prophylactic cranial irradiation (hazard ratio [HR] = 0.366, 95% confidence interval [CI] 0.20-0.66, P = 0.0008), and high ALI (HR = 0.475, 95% CI 0.27-0.84, P = 0.0103) were identified as independent prognostic factors for predicting better OS. Notably, a high ALI score was particularly indicative of longer survival in patients treated with the combination of etoposide and cisplatin. In conclusion, this study demonstrated that a high pretreatment ALI was significantly associated with better OS in patients with LS-SCLC undergoing definite CRT. This suggests that ALI could be a useful tool for predicting prognosis and guiding chemotherapy regimen selections in clinical practice for LS-SCLC.

EGF-conditioned M1 macrophages Convey reduced inflammation into corneal endothelial cells through exosomes.

Epidermal Growth Factor (EGF), a protein pivotal in cell proliferation and survival, has recently shown promise in alleviating inflammation. This study investigates EGF's impact on M1 macrophages, exploring its potential for anti-inflammatory and anti-vasculogenic interactions with corneal endothelial cells (CECs). Polarized M1 macrophages treated with EGF exhibited a suppression of gene expressions related to inflammatory and vasculogenic signals. The anti-inflammatory effects of EGF were observed in co-culture systems with human CECs (HCECs), showcasing its ability to alter macrophage phenotypes. Exosomes derived from EGF-treated M1 macrophages demonstrated enriched proteomic profiles related to immune system regulation and inflammation inhibition. When applied as eye drops in murine corneas, EGF-conditioned M1 macrophage-derived exosomes effectively reduced inflammation and increased M2-related ARG1 expression. This study highlights EGF's potential in mitigating inflammation in M1 macrophages and its delivery through exosomes to cultured HCECs and murine corneas, suggesting a novel therapeutic avenue for ocular surface anti-inflammatory treatments.

Parallel accumulation-serial fragmentation method for in-depth proteomic analysis of bronchoalveolar lavage fluid collected from patients with nonsmall cell lung cancer.

PURPOSE: Advances in mass spectrometry-based quantitative proteomic analysis have successfully demonstrated the in-depth detection of protein biomarkers in bronchoalveolar lavage fluid (BALF) from patients with lung cancers. Recently, ion mobility technology was incorporated into the mass spectrometers escalating the sensitivity and throughput. Utilizing these advantages, herein, we employed the parallel accumulation-serial fragmentation (PASEF) implanted in a timsTOF Pro mass spectrometer to examine the alteration of BALF proteomes in patients with nonsmall cell lung cancers (NSCLCs). EXPERIMENTAL DESIGN: BALF proteins were processed from patients with NSCLC and analyzed in a timsTOF Pro mass spectrometer with the PASEF method using a peptide input of 100 ng. Label-free mass spectrometry data were analyzed in the FragPipe platform. RESULTS: We quantitated over 1400 proteins from a single injection of 100 ng of peptides per sample with a median of ∼2000 proteins. We were able to find a few potential biomarker proteins upregulated in NSCLC. CONCLUSIONS AND CLINICAL RELEVANCE: The alterations of the BALF proteome landscape vary among patients with NSCLC as previously observed in patients with small-cell lung cancers. The PASEF method has significantly enhanced the sensitivity and throughput, demonstrating its effectiveness in clinical research and application.

Ocular surface parameter changes in the untreated fellow eye after unilateral cataract surgery with short-term administration of anti-inflammatory eye drops.

This study aimed to investigate the changes in clinical parameters of dry eye disease and meibomian gland dysfunction in both the operated and untreated fellow eyes of patients who underwent unilateral cataract surgery with the short-term administration of anti-inflammatory eye drops in the surgical eye. The medical charts of 57 consecutive patients who underwent unilateral cataract surgery and received 1% prednisolone acetate and non-steroidal anti-inflammatory drug (NSAID, 0.1% bromfenac sodium) eye drops were reviewed. The preoperative ocular surface disease index questionnaire score (38.9 ± 20.5) decreased significantly to 15.2 ± 16.4 at post-surgical 1 week and further to 12.8 ± 11.4 after 1 month. Although meibum quality grade increased and corneal sensitivity decreased at 1 week in operated eyes, corneal erosion scores and Sjogren's International Collaborative Clinical Alliance ocular staining scores even improved over a month in the untreated fellow eyes. The tear matrix metalloproteinase (MMP)-9 grade decreased in both operated eyes and untreated fellow eyes after 1 month from surgery. In conclusion, the short-term topical anti-inflammatory treatment using steroid and NSAID eye drops in the operated eye after cataract surgery decreased subjective ocular surface discomfort and improved ocular surface staining scores and tear MMP-9 expression in the untreated fellow eyes.

Real-World Treatment Outcomes and Safety of Afatinib in Advanced Squamous Cell Lung Cancer Progressed after Platinum-Based Doublet Chemotherapy and Immunotherapy (SPACE Study).

This study aimed to evaluate treatment outcomes and safety of afatinib in patients with squamous cell carcinoma of the lung (LSCC) who progressed after chemotherapy and immunotherapy. We recruited patients both retrospectively and prospectively and collected the outcomes and safety data. Additionally, we performed next-generation sequencing using tumor tissue and/or plasma to explore potential molecular biomarkers. Altogether, 42 patients were included in the final analysis. The median number of prior treatments was three (range 1-8), and the median TTF was 2.1 months. Objective response rate and disease control rate were 16.2% and 59.5%, respectively, and median duration of response was 4.0 months among response evaluable patients (n = 37). Treatment-related adverse events (TRAEs, including diarrhea, stomatitis, and paronychia) occurred in 22 (52.3%) patients; however, most were grade 2 or lower, and only 5 cases were grade 3. TRAEs led to dose modification in 17 (40.5%) and discontinuation in 4 (9.5%) patients. The TTF in patients with ERBB2 mutations was significantly longer than that in patients without (6.8 vs. 2.1 months, p = 0.045). Our results highlight that afatinib is a reasonable treatment option in terms of effectiveness and safety, and ERBB2 mutation can be used as a predictive biomarker in clinical settings.

The varied influence of ocular Demodex infestation on dry eye disease and meibomian gland dysfunction across different age groups.

This study aimed to investigate the impact of ocular demodicosis on dry eye disease (DED) and meibomian gland dysfunction (MGD) across different age populations: young (20 to < 40), middle-aged (40 to < 60), and elderly (≥ 60), based on the retrospective medical chart review. In each age subgroup, Demodex infestation and its count were correlated with clinical parameters of DED and MGD. Among the total of 351 subjects, 52.7% had ocular demodicosis, with a mean of 2.31 ± 1.39 mites per four eyelashes (0.58 per lash) in a unilateral eye. In the age subgroup 1 (age < 40; N = 44), subjects with Demodex had significantly higher meibum quality grades. In subgroup 2 (40 ≤ age < 60; N = 122), subjects with Demodex had higher ocular surface disease index scores and higher MG expressibility grades. However, in subgroup 3 (age ≥ 60; N = 185), demographics and all parameters did not differ according to Demodex infestation. Moreover, the number of mites did not correlate with MGD severity in any of the subgroups. In conclusion, age may act as a significant confounding factor in the relationship between ocular Demodex infestation and clinical features of DED and MGD, despite older patients aged 60 years and above being at a higher risk of Demodex infestation and experiencing more severe MGD.

Urban dust particles disrupt mitotic progression by dysregulating Aurora kinase B-related functions.

Particulate matter (PM), a major component of outdoor air pollution, damages DNA and increases the risk of cancer. Although the harmful effects of PM at the genomic level are known, the detailed mechanism by which PM affects chromosomal stability remains unclear. In this study, we investigated the novel effects of PM on mitotic progression and identified the underlying mechanisms. Gene set enrichment analysis of lung cancer patients residing in countries with high PM concentrations revealed the downregulation of genes associated with mitosis and mitotic structures. We also showed that exposure of lung cancer cells in vitro to urban dust particles (UDPs) inhibits cell proliferation through a prolonged M phase. The mitotic spindles in UDP-treated cells were hyperstabilized, and the number of centrioles increased. The rate of ingression of the cleavage furrow and actin clearance from the polar cortex was reduced significantly. The defects in mitotic progression were attributed to inactivation of Aurora B at kinetochore during early mitosis, and spindle midzone and midbody during late mitosis. While previous studies demonstrated possible links between PM and mitosis, they did not specifically identify the dysregulation of spatiotemporal dynamics of mitotic proteins and structures (e.g., microtubules, centrosomes, cleavage furrow, and equatorial and polar cortex), which results in the accumulation of chromosomal instability, ultimately contributing to carcinogenicity. The data highlight the novel scientific problem of PM-induced mitotic disruption. Additionally, we introduce a practical visual method for assessing the genotoxic outcomes of airborne pollutants, which has implications for future environmental and public health research.

Effective encoder-decoder neural network for segmentation of orbital tissue in computed tomography images of Graves' orbitopathy patients.

PURPOSE: To propose a neural network (NN) that can effectively segment orbital tissue in computed tomography (CT) images of Graves' orbitopathy (GO) patients. METHODS: We analyzed orbital CT scans from 701 GO patients diagnosed between 2010 and 2019 and devised an effective NN specializing in semantic orbital tissue segmentation in GO patients' CT images. After four conventional (Attention U-Net, DeepLab V3+, SegNet, and HarDNet-MSEG) and the proposed NN train the various manual orbital tissue segmentations, we calculated the Dice coefficient and Intersection over Union for comparison. RESULTS: CT images of the eyeball, four rectus muscles, the optic nerve, and the lacrimal gland tissues from all 701 patients were analyzed in this study. In the axial image with the largest eyeball area, the proposed NN achieved the best performance, with Dice coefficients of 98.2% for the eyeball, 94.1% for the optic nerve, 93.0% for the medial rectus muscle, and 91.1% for the lateral rectus muscle. The proposed NN also gave the best performance for the coronal image. Our qualitative analysis demonstrated that the proposed NN outputs provided more sophisticated orbital tissue segmentations for GO patients than the conventional NNs. CONCLUSION: We concluded that our proposed NN exhibited an improved CT image segmentation for GO patients over conventional NNs designed for semantic segmentation tasks.

Underestimation of smoking hazards and smoking cessation intervention efficiency among healthcare professionals: A cross-sectional study among Korean occupational health nurses.

INTRODUCTION: Occupational health nurses (OHNs) in South Korea who visit the workplace periodically could play a key role in smoking cessation. It would be helpful to assess their understanding of smoking hazards and smoking cessation methods to encourage them to provide smoking intervention services at the workplace. This study aimed to investigate the knowledge of smoking hazards and perceptions of smoking cessation methods among OHNs. METHODS: We conducted an anonymous self-administered cross-sectional questionnaire survey of 108 OHN nurses employed in an occupational health service outsourcing specialized agency with 19 regional branches in Korea from July to August 2019. We assessed the perceptions of the OHNs about smoking interventions, hazards of smoking, and perceived competence to counsel smokers according to training experience, using chi-squared tests and Fisher's exact tests. RESULTS: The majority of the nurses underestimated the smoking-attributable fraction for lung cancer (78.7%), chronic obstructive pulmonary disease (64.8%), and mortality (49.0%), regardless of training experience on smoking cessation, while more than half perceived their skill and knowledge to counsel patients concerning smoking as inadequate (56.5%). However, those trained in smoking cessation interventions felt more competent in smoking cessation counselling, with 52.2% and 29.3% in the trained and non-trained groups, respectively (p=0.019). CONCLUSIONS: The OHNs in this study underestimated smoking hazards and perceived themselves as lacking counselling skills regarding smoking cessation interventions. It is necessary to encourage OHNs to promote smoking cessation by increasing their knowledge, skills and competence in smoking cessation interventions.

Mild exposure to fine particulate matter promotes angiogenesis in non-small cell lung carcinoma.

Fine particulate matter (PM2.5) is associated with public health problems worldwide. Especially, PM2.5 induces epigenetic and microenvironmental changes in lung cancer. Angiogenesis is important for the development and growth of cancer and is mediated by angiogenic factors, including vascular endothelial growth factor. However, the effects of mild PM2.5 exposure on angiogenesis in lung cancer remain unclear. In this study, we examined angiogenic effects using relatively lower concentrations of PM2.5 than in other studies and found that PM2.5 increased angiogenic activities in both endothelial cells and non-small cell lung carcinoma cells. PM2.5 also promoted the growth and angiogenesis of lung cancer via the induction of hypoxia-inducible factor-1α (HIF-1α) in a xenograft mouse tumor model. Angiogenic factors, including vascular endothelial growth factor (VEGF), were highly expressed in lung cancer patients in countries with high PM2.5 levels in the atmosphere, and high expression of VEGF in lung cancer patients lowered the survival rate. Collectively, these results provide new insight into the mechanisms by which mild exposure to PM2.5 is involved in HIF-1α-mediated angiogenesis in lung cancer patients.

Safety and Efficacy of Bojungikki-Tang in Advanced NSCLC Patients Receiving Treatment with Immune Checkpoint Inhibitors: Protocol for a Multicenter, Double-Blind, Randomized, Placebo-Controlled Pilot Trial.

Cancer immunotherapy with immune checkpoint inhibitors (ICIs) is a major treatment option for several types of cancer, including non-small cell lung cancer (NSCLC). The proposed study aims to investigate the safety and efficacy of Bojungikki-tang (BJIKT) therapy (an herbal medicine) in patients with advanced NSCLC treated with ICIs. This multicenter, randomized, placebo-controlled pilot study will be performed at three academic hospitals. Thirty patients with advanced NSCLC, undergoing atezolizumab monotherapy as second- and subsequent-line treatment, will be recruited and randomly assigned to either BJIKT treatment (atezolizumab + BJIKT) or placebo (atezolizumab + placebo). The primary and secondary outcomes are the incidence of adverse events (AEs), including immune- related AEs (irAEs) and non-immune-related AEs (non-irAEs); and early termination rate, withdrawal period, symptom improvement of fatigue, and skeletal muscle loss, respectively. The exploratory outcomes are patient objective response rate and immune profile. This is an ongoing trial. Recruitment started on 25 March 2022 and is expected to be completed by 30 June 2023. This study will provide basic evidence for the safety profiles, including irAEs, of herbal medicine in patients with advanced NSCLC treated with ICIs.

Influence of 0.002% Omidenepag Isopropyl on Intraocular Pressure and the Cornea in Normal Tension Glaucoma.

PRCIS: Although Omidenepag isopropyl drops elicited stable intraocular pressure reductions in NTG patients, transient changes in refraction and corneal endothelial cells, significant increase of central corneal thickness, and corneal erosion should be considered. PURPOSE: To analyze the efficacy and safety of 0.002% omidenepag Isopropyl (OMDI) eye drops in patients with normal tension glaucoma (NTG). METHODS: Medical records for 62 eyes treated with OMDI for ≥6 months were analyzed. Intraocular pressure (IOP), refraction, keratometry, central corneal thickness (CCT), endothelial cell count, coefficient of variation of endothelial cell area (CV), corneal erosion, and central retinal thickness were compared at baseline and 1, 3, and 6 months. RESULTS: IOP significantly decreased from 13.4±3.8 to 11.9±3.0, 11.7±2.9, and 12.2±3.3 mm Hg at each follow-up ( P <0.001). Endothelial cell count did not change, but CV transiently increased from 12.6 to 17.0 at 1 month, CCT increased from 531.5 to 538.4 µm, myopia changed from -1.5 to -1.9 D, and keratometry changed from 44.5 to 44.7 D. CV, myopia, and keratometry recovered to baseline at 6 months; however, CCT remained high. Significant corneal erosion was observed at 6 months. Central retinal thickness changes were not observed. There were improvements in prostaglandin-associated skin pigmentation (86.7%), eyelash elongation (40.0%), and deepening of the upper eyelid sulcus and ptosis (~30%) at 3 months after exchange to OMDI. Adverse reactions were corneal erosion (27.4%), corneal thickening (21.0%), conjunctival hyperemia (11.3%), photophobia (5.7%), blurred vision (5.7%), and anterior chamber cells (4.8%). CONCLUSIONS: OMDI eye drops elicited significant and stable IOP reductions after 6 months in NTG patients with low IOP. However, transient myopic and corneal endothelial cell changes, development of corneal thickening, and corneal erosion should be considered when using OMDI.

Quantitative proteomic analysis of bronchoalveolar lavage fluids from patients with small cell lung cancers.

PURPOSE: Small cell lung cancer (SCLC) is one of the malignant cancers with aggressive progression and poor prognosis. Bronchoalveolar lavage fluid (BALF) has been arising recently as a potential source of biomarkers for lung cancers. In this study, we performed quantitative BALF proteomic analysis to identify potential biomarkers for SCLC. EXPERIMENTAL DESIGN: BALF were collected from tumor-bearing lungs and non-tumor lungs of five SCLC patients. Then, BALF proteomes were prepared for a TMT-based quantitative mass spectrometry analysis. Differentially expressed proteins (DEP) were identified when considering individual variation. Potential SCLC biomarker candidates were validated by immunohistochemistry (IHC). A public database of multiple SCLC cell lines was used to evaluate the correlation of these markers with SCLC subtypes and chemo-drug responses. RESULTS: We identified 460 BALF proteins in SCLC patients and observed considerable individual variation among the patients. Immunohistochemical analysis and bioinformatics resulted in the identification of CNDP2 and RNPEP as potential subtype markers for ASCL1 and NEUROD1, respectively. In addition, CNDP2 was found to be positively correlated with responses to etoposide, carboplatin, and irinotecan. CONCLUSIONS AND CLINICAL RELEVANCE: BALF is an emerging source of biomarkers, making it useful for the diagnosis and prognosis of lung cancers. We characterized the proteomes of paired BALF samples collected from tumor-bearing and non-tumor lungs of SCLC patients. Several proteins were found elevated in tumor-bearing BALF, and especially CNDP2 and RNPEP appeared to be potential indicators for ASLC1-high and NEUROD1-high subtypes of SCLC, respectively. The positive correlation of CNDP2 with chemo-drug responses would help to make decisions for treatment of SCLC patients. These putative biomarkers could be comprehensively investigated for a clinical use towards precision medicine.

Real-World Study of Osimertinib in Korean Patients with Epidermal Growth Factor Receptor T790M Mutation-Positive Non-Small Cell Lung Cancer.

PURPOSE: Although osimertinib is the standard-of-care treatment of epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer, real-world evidence on the efficacy of osimertinib is not enough to reflect the complexity of the entire course of treatment. Herein, we report on the use of osimertinib in patients with EGFR T790M mutation-positive non-small cell lung cancer who had previously received EGFR tyrosine kinase inhibitor (TKI) treatment in Korea. MATERIALS AND METHODS: Patients with confirmed EGFR T790M after disease progression of prior EGFR-TKI were enrolled and administered osimertinib 80 mg daily. The primary effectiveness outcome was progression-free survival, with time-to-treatment discontinuation, treatment and adverse effects leading to treatment discontinuation, and overall survival being the secondary endpoints. RESULTS: A total of 558 individuals were enrolled, and 55.2% had investigator-assessed responses. The median progression-free survival was 14.2 months (95% confidence interval [CI], 13.0 to 16.4), and the median time-to-treatment discontinuation was 15.0 months (95% CI, 14.1 to 15.9). The median overall survival was 36.7 months (95% CI, 30.9 to not reached). The benefit with osimertinib was consistent regardless of the age, sex, smoking history, and primary EGFR mutation subtype. However, hepatic metastases at the time of diagnosis, the presence of plasma EGFR T790M, and the shorter duration of prior EGFR-TKI treatment were poor predictors of osimertinib treatment. Ten patients (1.8%), including three with pneumonitis, had to discontinue osimertinib due to severe adverse effects. CONCLUSION: Osimertinib demonstrated its clinical effectiveness and survival benefit for EGFR T790M mutation-positive in Korean patients with no new safety signals.

Hyper- and hypo-perfusion of choriocapillaris in the eyes with pachychoroid pigment epitheliopathy.

PURPOSE: To evaluate the changes in choriocapillaris vessel density (VD) in eyes with pachychoroid pigment epitheliopathy (PPE) using swept-source optical coherence tomography (OCT) angiography (OCTA). METHODS: This study included 83 eyes with PPE and 42 control eyes. We collected OCT and OCTA parameters, including central point thickness, subfoveal choroidal thickness (SFChT), and choriocapillaris VD of the fovea (CC fovea) and parafovea. The parafoveal area was divided into superior, nasal, inferior, and temporal choriocapillaris areas. Maximum (CC max) and minimum (CC min) choriocapillaris VD were defined as the highest and lowest values among the four parafoveal subfield VDs, respectively. We analyzed the average choriocapillaris VD, CC max, CC min, CC fovea, and the difference between CC max and CC min (CC delta) individually and compared all the parameters between PPE and control eyes. RESULTS: CC max (56.0% ± 1.7%) was significantly higher and CC min (50.9% ± 2.0%) significantly lower in eyes with PPE than in control eyes (CC max, 55.3% ± 1.0%, P = 0.006; CC min, 51.5% ± 1.3%, P = 0.046). The CC delta value (5.0% ± 2.1%) and SFChT (389.9 ± 129.9 µm) were also significantly higher in eyes with PPE than in the control group (3.7% ± 1.5%, P < 0.001; 268.2 ± 102.2 µm, P < 0.001; respectively). CONCLUSIONS: Choriocapillaris VD showed higher variability (hyperperfusion and hypoperfusion) in eyes with PPE than in control eyes. Choriocapillaris hypoperfusion may precede the development of PPE; however, choriocapillaris hyperperfusion is associated with projection artifacts.

Read Count Patterns and Detection of Cancerous Copy Number Alterations in Plasma Cell-Free DNA Whole Exome Sequencing Data for Advanced Non-Small Cell Lung Cancer.

Plasma cell-free DNA (cfDNA) sequencing data have been widely studied for early diagnosis and treatment response or recurrence monitoring of cancers because of the non-invasive benefits. In cancer studies, whole exome sequencing (WES) is mostly used for discovering single nucleotide variants (SNVs), but it also has the potential to detect copy number alterations (CNAs) that are mostly discovered by whole genome sequencing or microarray. In clinical settings where the quantity of the acquired blood from the patients is limited and where various sequencing experiments are not possible, providing various types of mutation information such as CNAs and SNVs using only WES will be helpful in the treatment decision. Here, we questioned whether the plasma cfDNA WES data for patients with advanced non-small cell lung cancer (NSCLC) could be exploited for CNA detection. When the read count (RC) signals of the WES data were investigated, a similar fluctuation pattern was observed among the signals of different samples, and it can be a major challenge hindering CNA detection. When these RC patterns among cfDNA were suppressed by the method we proposed, the cancerous CNAs were more distinguishable in some samples with higher cfDNA quantity. Although the potential to detect CNAs using the plasma cfDNA WES data for NSCLC patients was studied here, further studies with other cancer types, with more samples, and with more sophisticated techniques for bias correction are required to confirm our observation. In conclusion, the detection performance for cancerous CNAs can be improved by controlling RC bias, but it depends on the quantity of cfDNA in plasma.