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Background: Carcinogenesis is a multistep process, which may begin as a consequence of chromosomal changes. Deletions in the short arm of chromosome 9 (9p) have been observed in lung carcinomas. In addition, morphologically recognizable preneoplastic lesions, frequently multiple in number, precede onset of invasive carcinomas.Purpose: We tested for deletions and loss of heterozygosity (LOH) at 9p loci in preneoplastic and neoplastic foci in lungs of patients with non-small-cell lung carcinomas (NSCLCs).Methods: Seven archival, paraffin-embedded, surgically resected NSCLC specimens were selected. They were predominantly from patients with adenocarcinomas and contained multiple preneoplastic lesions, including hyperplasia, metaplasia, dysplasia, and carcinoma in situ (CIS). Fifty-three histologically identified preneoplastic and malignant lesions present in bronchi, bronchioles, and alveoli were precisely microdissected from stained tissue sections with a micromanipulator. Stromal lymphocytes were used to determine constitutional heterozygosity. The specimens were analyzed for LOH using polymerase chain reaction-based assays for polymorphism in dinucleotide repeats (microsatellite markers) in interferon alfa (IFNA) and D9S171 loci on 9p.Results: All seven cases were constitutionally heterozygous for one or both microsatellite markers. Five of seven cases had LOH at one or both 9p loci in the invasive primary cancers (doubly informative cases). Four of these five cases also revealed LOH in preneoplastic foci. In the doubly informative cases, LOH was detected in five (38%) of 13 foci of hyperplasia, four (80%) of five foci of dysplasia, and three (100%) of three CIS lesions. LOH was detected in preneoplastic lesions from all regions of the respiratory tract, including bronchi, bronchioles, and alveoli, and involved five different cell types. The identical allele was lost from both the preneoplastic lesions and the corresponding tumors (12 of 12 lesions, 17 of 17 comparisons), a phenomenon we have referred to as "allele-specific mutation." Statistical analyses employing a cumulative binomial test demonstrated that the probabilities of such findings occurring by chance are 2.4 x 10(-4) and 7.6 x 10(-6), respectively. From comparisons with the previously published data on other chromosomal abnormalities in the same tissue specimens, it appears that LOH at 3p and 9p loci occurred early in the hyperplasia stage, but the ras gene point mutations were relatively late, at the CIS stage.Conclusions: LOH at 9p loci occurs at the earliest stage in the pathogenesis of lung cancer and involves all regions of the respiratory tract. LOH in NSCLC is not random but targets a specific allele in individuals. Studying preneoplastic lesions may help identify intermediate markers for risk assessment and chemoprevention. [ABSTRACT FROM AUTHOR]

Musashi1 (Msi1) is an RNA binding protein with a central role during nervous system development and stem cell maintenance. High levels of Msi1 have been reported in several malignancies including brain tumors thereby associating Msi1 and cancer.~Background~Background~We used the human medulloblastoma cell line Daoy as model system in this study to knock down the expression of Msi1 and determine the effects upon soft agar growth and neurophere formation. Quantitative RT-PCR was conducted to evaluate the expression of cell proliferation, differentiation and survival genes in Msi1 depleted Daoy cells.~Methods~Methods~We observed that MSI1 expression was elevated in Daoy cells cultured as neurospheres compared to those grown as monolayer. These data indicated that Msi1 might be involved in regulating proliferation in cancer cells. Here we show that shRNA mediated Msi1 depletion in Daoy cells notably impaired their ability to form colonies in soft agar and to grow as neurospheres in culture. Moreover, differential expression of a group of Notch, Hedgehog and Wnt pathway related genes including MYCN, FOS, NOTCH2, SMO, CDKN1A, CCND2, CCND1, and DKK1, was also found in the Msi1 knockdown, demonstrating that Msi1 modulated the expression of a subset of cell proliferation, differentiation and survival genes in Daoy.~Results~Results~Our data suggested that Msi1 may promote cancer cell proliferation and survival as its loss seems to have a detrimental effect in the maintenance of medulloblastoma cancer cells. In this regard, Msi1 might be a positive regulator of tumor progression and a potential target for therapy.~Conclusion~Conclusions [ABSTRACT FROM AUTHOR]

Purposes: Chronic obstructive pulmonary disease (COPD) is a major cause of the rapid decline of health-related quality of life (HRQoL), associated with accelerated frailty in older populations. This study aimed to analyse the long-term dynamic changes of HRQoL and the predictive factors for the rapid decline of HRQoL in older patients with COPD., Methods: Overall 244 patients with COPD, aged ≧ 65 years from one medical centre were enrolled between March 2012 and July 2020. Further, we prospectively assessed HRQoL scores with utility values, using EuroQol Five-Dimension (EQ-5D) questionnaires. Additionally, long-term dynamic changes in HRQoL were analysed using the Kernel smoothing method and examined the factors contributing to the deterioration of HRQoL using a linear mixed effects model., Results: Older patients with COPD with forced expiration volume (FEV1) < 50% of prediction entered the phase of rapid and continuous decline of HRQoL ~ 2 years after enrolment, but patients with FEV1 ≥ 50% of prediction without rapidly declined HRQoL during 7 years follow up. Therefore, FEV1 < 50% of prediction is a novel predictor for the rapid decline of HRQoL. The course of rapidly declining HRQoL occurred, initially in the usual activities and pain/discomfort domains, followed by the morbidity, self-care, and depression/anxiety domains ~ 2 and 4 years after enrolment, respectively. The mixed effects model indicated that both FEV1 < 50% of prediction and a history of severe acute exacerbation (SAE) requiring hospitalisation were contributing factors for deterioration in HRQoL ., Conclusions: Both FEV1 < 50% of prediction and exacerbations requiring hospitalisation were contributing factors for the deterioration of HRQoL in long-term follow up. Additionally, FEV1 < 50% of prediction was a novel predictor for patients entering the phase of rapid decline of HRQoL., (© 2024. The Author(s).)

Hepatitis E virus (HEV) variants infecting humans belong to two species: Paslahepevirus balayani (bHEV) and Rocahepevirus ratti (rat hepatitis E virus; rHEV). R. ratti is a ubiquitous rodent pathogen that has recently been recognized to cause hepatitis in humans. Transmission routes of rHEV from rats to humans are currently unknown. In this study, we examined rHEV exposure in cats and dogs to determine if they are potential reservoirs of this emerging human pathogen. Virus-like particle-based IgG enzymatic immunoassays (EIAs) capable of differentiating rHEV & bHEV antibody profiles and rHEV-specific real-time RT-PCR assays were used for this purpose. The EIAs could detect bHEV and rHEV patient-derived IgG spiked in dog and cat sera. Sera from 751 companion dogs and 130 companion cats in Hong Kong were tested with these IgG enzymatic immunoassays (EIAs). Overall, 13/751 (1.7%) dogs and 5/130 (3.8%) cats were sero-reactive to HEV. 9/751 (1.2%) dogs and 2/130 (1.5%) cats tested positive for rHEV IgG, which was further confirmed by rHEV immunoblots. Most rHEV-seropositive animals were from areas in or adjacent to districts reporting human rHEV infection. Neither 881 companion animals nor 652 stray animals carried rHEV RNA in serum or rectal swabs. Therefore, we could not confirm a role for cats and dogs in transmitting rHEV to humans. Further work is required to understand the reasons for low-level seropositivity in these animals.

The targeted capture of ultraconserved elements (UCEs) has substantially increased the amount of genetic data available for phylogenomic reconstructions. These capture datasets frequently contain mitochondrial DNA as a by-product, often in the form of complete mitogenomes. These can be efficiently harvested to expand existing datasets without additional costs. Here, we present new mitochondrial genomes for six marine angelfish species (F: Pomacanthidae), assembled and annotated from off-target UCE reads. We provide the first comparative analysis of all mitochondrial genomes available for the Pomacanthidae. Results showed that the average length of pomacanthid mitogenomes is 16.8 kbp. Total GC and AT content varied between 44.5% and 46.3%, and 53.7% and 55.5%, respectively. The architecture of angelfish mitogenomes was comparable to that seen in other fish species with 13 protein-coding genes (PCGs), 22 transfer RNA genes, two ribosomal RNA genes and the control region. All 13 PCGs evolved under purifying selection, highlighting a high level of selection pressure and gene expression to preserve genetic integrity. The ND6 and ATP8 genes had the highest ratio of non-synonymous (dN) to synonymous (dS) substitutions, indicating a relaxation of purifying selection constraints. Finally, these newly assembled mitogenomes will allow further investigations of the population genetics, systematics and evolutionary biology of one of the most prominent reef fish family in the aquarium trade., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Author(s). Ecology and Evolution published by John Wiley & Sons Ltd.)

Osimertinib has demonstrated efficacy in patients with epidermal growth factor receptor (EGFR) T790M-positive non-small cell lung cancer (NSCLC) in clinical trials. However, real-world data on its effectiveness remain scarce. Taiwanese patients with T790M-positive locally advanced or metastatic NSCLC and progressive disease following treatment with at least one EGFR tyrosine kinase inhibitor (TKI) were enrolled from the osimertinib early access program. Of the 419 patients (mean age, 63 years; female, 67%), 53% were heavily pretreated (≥ third-line [3L]), making osimertinib a fourth-line (4L) intervention. The median progression-free survival (PFS) was 10.5 months (95% confidence interval [CI]: 8.95-11.41); the 18-month PFS rate was 26.5%. The median overall survival (OS) was 19.0 months (95% CI: 16.30-20.95); the 24-month OS rate was 40.9%. The objective response rate was 32.46%, and the disease control rate was 86.38%. The median time to treatment discontinuation of osimertinib monotherapy was 11.9 months (95% CI: 10.49-13.11). Subgroup analyses of median PFS and OS in the chemotherapy combination group vs. the osimertinib monotherapy group yielded no difference. Central nervous system (CNS) metastasis, number of prior lines of therapy, and types of initial EGFR-TKIs did not significantly impact outcomes. The median PFS values were 9.0 (95% CI: 5.18-11.34) and 10.9 (95% CI: 9.18-11.90) months with and without CNS metastasis, respectively, and 10.8 (95% CI: 8.59-12.69), 13.6 (95% CI: 10.89-16.3), and 9.2 (95% CI: 7.8-10.62) months for second-line (2L), 3L, and ≥4L therapy, respectively. In patients who received osimertinib as 2L therapy, the median PFS values in response to prior afatinib, erlotinib and gefitinib treatment were 11.2 (95% CI: 4.85-4.79), 10.5 (95% CI: 8.59-20.26) and 8.7 (95% CI: 7.21-16.79) months, respectively. Overall, real-world data from Taiwan support the clinical benefits of osimertinib in EGFR T790M -positive NSCLC., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Chang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Combining epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) with an anti- vascular endothelial growth factor (VEGF) agent, bevacizumab or ramucirumab, is indicated for advanced lung adenocarcinoma harboring EGFR mutation. This study aimed to show the real-world data of combination therapy and compare the effectiveness between bevacizumab and ramucirumab in combination with an EGFR-TKI. This retrospective study enrolled 47 patients diagnosed of stage IV lung adenocarcinoma with exon 19 deletion or L858R point mutation, receiving a first-line EGFR-TKI with anti-VEGF agent, including 34 (72%) and 13 (28%) patients receiving bevacizumab and ramucirumab, respectively. The response rate was similar in both groups (p = 0.38). Patients receiving bevacizumab had similar progression free survival (PFS) as those receiving ramucirumab (median PFS: 21.9 vs. 24.2 months, p = 0.4871); similar finding was noted in overall survival (OS) (median OS: 33.5 months vs. not reached, p = 0.4618). Patients receiving ramucirumab experienced a significantly high-grade hypertension compared to those receiving bevacizumab (p = 0.0351). Multivariable Cox regression analysis found independent risk factors for worse PFS included poorer ECOG performance status, multiple (≥3) metastatic sites, brain metastasis, and pleural metastasis/effusion, while the type of anti-VEGF agent was not a risk factor. Pericardial metastasis/effusion was the only one independent risk factor for worse OS. In summary, ramucirumab may have similar effectiveness as bevacizumab in combination with an EGFR-TKI as first line therapy for advanced lung adenocarcinoma harboring susceptible EGFR mutation. Further large-scale registry-based cohort studies may be needed to validate our findings., (© 2024 The Authors. The Kaohsiung Journal of Medical Sciences published by John Wiley & Sons Australia, Ltd on behalf of Kaohsiung Medical University.)

Lung squamous cell carcinoma (LUSC) remains a difficult-to-treat disease with a poor prognosis. While prominin-1 ( PROM1/CD-133 ) is largely investigated in a variety of malignancies, the role of prominin-2 ( PROM2 ), the other member of the prominin family, has not been studied in LUSC. Transcriptomic data derived from matched tumor and adjacent non-tumorous lung tissues of LUSC patients were employed to conduct an in-depth analysis of the genetic and epigenetic regulation of prominin genes within LUSC, utilizing bioinformatic approaches. Furthermore, cellular behavior experiments were executed to discern the biological functions of PROM2 . It was observed that PROM2 , in contrast to PROM1 , exhibited significant upregulation and overexpression at both the mRNA and protein levels in LUSC, and this upregulation was correlated with shortened patient survival. Transcriptomic analysis unveiled DNA methylation as an epigenetic regulatory mechanism associated with PROM2 expression. Notably, two transcription factors, CBFB and NRIP1 , were identified as potential regulators of PROM2 expression. Subsequent in vitro investigations demonstrated that knocking down PROM2 led to the inhibition of cancer cell migration and the epithelial-to-mesenchymal transition (EMT). In summary, the pronounced upregulation of PROM2 in LUSC patients was linked to an unfavorable prognosis, possibly attributable to its influence on cancer cell migration and EMT. These findings suggest that PROM2 could serve as a promising diagnostic biomarker and therapeutic target in the management of LUSC. Consequently, further research into the mechanistic aspects and potential therapeutic interventions targeting PROM2 is warranted in the clinical context., Competing Interests: None., (AJCR Copyright © 2024.)

Background: The life trajectory of chronic obstructive pulmonary disease (COPD) remains unknown., Patients and Methods: We collected data from two populations. In the first cohort, we recruited 375 patients with COPD from our hospital, and 1440 repeated assessments of quality of life (QoL) using the European Quality of Life-5 Dimensions questionnaire from 2006 to 2020. We analysed their dynamic changes using the kernel-smoothing method. The second cohort comprised 27 437 patients from the National Health Insurance (NHI) dataset with their first severe acute exacerbations (AEs) requiring hospitalisation from 2008 to 2017 were analysed for their long-term course of AEs. We employed a Cox hazard model to analyse the predictors for mortality or AEs., Results: Cohorts from our hospital and NHI were male predominant (93.6 and 83.5%, respectively). After the first severe AE, the course generally comprised three phases. The first was a 1-year period of elevated QoL, followed by a 2-year prolonged stable phase with a slowly declining QoL. After the second AE, the final phase was characterised by a rapid decline in QoL. For NHI cohort, 2712 died during the 11-year follow-up, the frequency of the first AE was approximately 5 per 10 000 per day. The median time from the first to the second AE was 3 years, which decreased to less than 6 and 3 months from 4th to 5th and 8th to 9th AE, respectively. The frequency of AE was increased 10-fold and 15-fold and risk of subsequent AE was increased 12-fold and 20-fold after the 6th and the 10th AE, relative to the first. Male gender, heart failure comorbidities were associated with the risk of subsequent AE and death., Conclusions: The life trajectory of COPD includes the accelerated frailty phase, as well as elevated health and prolonged stable phase after the first AE., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The poor outcome of patients with lung adenocarcinoma (LUAD) highlights the importance to identify novel effective prognostic markers and therapeutic targets. Long noncoding RNAs (lncRNAs) have generally been considered to serve important roles in tumorigenesis and the development of various types of cancer, including LUAD. Here, we aimed to investigate the role of ENTPD3-AS1 (ENTPD3 Antisense RNA 1) in LUAD and to explore its potential mechanisms by performing comprehensive bioinformatic analyses. The regulatory effect of ENTPD3-AS1 on the expression of NR3C1 was validated by siRNA-based silencing. The effect of miR-421 on the modulation of NR3C1 was determined by miRNA mimics and inhibitors transfection. ENTPD3-AS1 was expressed at lower levels in tumor parts and negatively correlated with unfavorable prognosis in LUAD patients. It exerted functions as a tumor suppressor gene by competitively binding to oncomir, miR-421, thereby attenuating NR3C1 expression. Transfection of lung cancer A549 cells with miR-421 mimics decreased the expression of NR3C1 . Transfection of lung cancer A549 cells with miR-421 inhibitors increased the expression of NR3C1 with lower cellular functions as proliferation and migration via epithelial-mesenchymal transition. In addition, inhibition of ENTPD3-AS1 by siRNA transfection decreased the levels of NR3C1 , supporting the ENTPD3-AS1 /miR-421/NR3C1 cascade. Moreover, the bioinformatic analysis also showed that ENTPD3-AS1 could interact with the RNA-binding proteins (RBPs), CELF2 and QKI, consequently regulating RNA expression and processing. Taken together, we identified that ENTPD3-AS1 and its indirect target NR3C1 can act as novel biomarkers for determining the prognosis of patients with LUAD, and further study is required., Competing Interests: None., (AJCR Copyright © 2024.)

Lung adenocarcinoma (LUAD) is one of the deadliest cancers regarding both mortality rate and number of deaths and warrants greater effort in the development of potential therapeutic targets. The enhancer of rudimentary homolog ( ERH ) has been implicated in the promotion and progression of certain types of cancer. In the present study, ERH was assessed for its expression pattern and survival association with LUAD in public transcriptomic and proteomic databases. Bioinformatic methods and data from websites, including University of Alabama at Birmingham CANcer data analysis Portal and The Cancer Genome Atlas, were utilized to demonstrate the functional behaviors and corresponding pathways of ERH in LUAD. Human A549 and CL1‑0 cell lines were used to validate the findings via functional assays. It was demonstrated that the expression of ERH, at both the transcriptomic and proteomic levels, was higher in LUAD compared with in adjacent non‑tumor lung tissue and was associated with worse survival prognosis. Moreover, high ERH expression was correlated with more aggressive functional states, such as cell cycle and invasion in LUAD, and the positive ERH ‑correlated gene set was associated with worse survival and an immunosuppressive tumor microenvironment. Small nuclear ribonucleoprotein polypeptide G was identified as a molecule that potentially interacted with ERH . Lastly, it was demonstrated that ERH promoted epithelial‑mesenchymal transition and cell migration in vitro , but not proliferation. In conclusion, higher expression of ERH in LUAD may facilitate cancer progression and confer worse outcomes. Further deep investigation into the role of ERH in LUAD is needed.

Importance: Clarifying the relationship between kindergarteners' characteristics and their future handwriting performance is beneficial for the early detection of children at risk of handwriting difficulties., Objective: To determine which visual-perceptual and motor skills and behavioral traits significantly predict kindergartners' Chinese handwriting legibility and speed in the first grade., Design: One-year longitudinal, observational design., Setting: Kindergarten and elementary schools., Participants: One hundred six kindergarten children (53 boys and 53 girls; ages 5 or 6 yr) were recruited., Outcomes and Measures: The participants completed two subtests of the Bruininks-Oseretsky Test of Motor Proficiency-Second Edition, Test of Visual Perceptual Skills-Third Edition, Beery-Buktenica Developmental Test of Visual-Motor Integration (Beery™ VMI), and the Attention-Deficit/Hyperactivity Disorder Test-Chinese Version in kindergarten. Their handwriting legibility (character accuracy and construction) and speed were assessed by investigator-developed Chinese handwriting tests in the first grade., Results: Multivariate regression analyses indicated the independent predictive power of spatial relationships (p = .042) and inattention (p = .004) for character accuracy. Visual-motor integration (VMI; p = .008) and inattention (p = .002) were the key predictors of character construction. Manual dexterity (p = .001) was the only significant predictor of writing speed., Conclusions and Relevance: Kindergarteners who perform poorly in spatial relationships, VMI, manual dexterity, and attention are likely to have less legible Chinese handwriting and slow writing speed in first grade. Plain-Language Summary: Children's visual-perceptual and motor skills and behavioral traits in kindergarten can predict their Chinese handwriting legibility and speed in first grade. This study found that kindergarteners who performed poorly in spatial relationships, VMI, manual dexterity, and attention were likely to have less legible Chinese handwriting and slow writing speed in the first grade., (Copyright © 2024 by the American Occupational Therapy Association, Inc.)

Background: Amivantamab has been approved for the treatment of patients with advanced non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor ( EGFR ) exon 20 insertions who have had disease progression during or after platinum-based chemotherapy. Phase 1 data showed the safety and antitumor activity of amivantamab plus carboplatin-pemetrexed (chemotherapy). Additional data on this combination therapy are needed., Methods: In this phase 3, international, randomized trial, we assigned in a 1:1 ratio patients with advanced NSCLC with EGFR exon 20 insertions who had not received previous systemic therapy to receive intravenous amivantamab plus chemotherapy (amivantamab-chemotherapy) or chemotherapy alone. The primary outcome was progression-free survival according to blinded independent central review. Patients in the chemotherapy group who had disease progression were allowed to cross over to receive amivantamab monotherapy., Results: A total of 308 patients underwent randomization (153 to receive amivantamab-chemotherapy and 155 to receive chemotherapy alone). Progression-free survival was significantly longer in the amivantamab-chemotherapy group than in the chemotherapy group (median, 11.4 months and 6.7 months, respectively; hazard ratio for disease progression or death, 0.40; 95% confidence interval [CI], 0.30 to 0.53; P<0.001). At 18 months, progression-free survival was reported in 31% of the patients in the amivantamab-chemotherapy group and in 3% in the chemotherapy group; a complete or partial response at data cutoff was reported in 73% and 47%, respectively (rate ratio, 1.50; 95% CI, 1.32 to 1.68; P<0.001). In the interim overall survival analysis (33% maturity), the hazard ratio for death for amivantamab-chemotherapy as compared with chemotherapy was 0.67 (95% CI, 0.42 to 1.09; P = 0.11). The predominant adverse events associated with amivantamab-chemotherapy were reversible hematologic and EGFR-related toxic effects; 7% of patients discontinued amivantamab owing to adverse reactions., Conclusions: The use of amivantamab-chemotherapy resulted in superior efficacy as compared with chemotherapy alone as first-line treatment of patients with advanced NSCLC with EGFR exon 20 insertions. (Funded by Janssen Research and Development; PAPILLON ClinicalTrials.gov number, NCT04538664.)., (Copyright © 2023 Massachusetts Medical Society.)

Background: Dementia is a prevalent condition in type 2 diabetes mellitus (T2DM) patients. While Chinese herbal medicine (CHM) is often employed as complementary therapy for glycemic control, its effect in controlling likelihood of dementia has not yet been fully elucidated., Aim: To compare the risk of dementia between T2DM patients with and without CHM treatment., Methods: We undertook a nested case-control study and obtained data on patients 20-70 years of age who received medical care for T2DM between 2001 and 2010 from the National Health Insurance Research database in Taiwan. Cases, defined as those with dementia that occurred at least one year after the diagnosis of T2DM, were randomly matched to controls without dementia from the study cohort at a 1:1 ratio. We applied conditional logistic regression to explore the associations between CHM treatment and dementia., Results: A total of 11699 dementia cases were matched to 11699 non-dementia controls. We found that adding CHM to conventional care was related to a lower risk of dementia [adjusted odds ratio (OR) = 0.51], and high-intensity CHM treatment was associated with an adjusted OR of 0.22., Conclusion: This study shows that the cumulative CHM exposure was inversely associated with dementia risk in an exposure-response manner, implying that CHM treatment may be embraced as a disease management approach for diabetic patients to prevent dementia., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Lung cancer is associated with a high mortality rate and often complicated with malignant pleural effusion (MPE), which has a very poor clinical outcome with a short life expectancy. However, our understanding of cell-specific mechanisms underlying the pathobiology of pleural metastasis remains incomplete. Methods: We analyzed single-cell transcriptomes of cells in pleural effusion collected from patients with lung cancer and congestive heart failure (as a control), respectively. Soluble and complement factors were measured using a multiplex cytokine bead assay. The role of ferroptosis was evaluated by GPX4 small interfering RNA (siRNA) transfection and overexpression. Results: We found that the mesothelial-mesenchymal transition (MesoMT) of the pleural mesothelial cells contributed to pleural metastasis, which was validated by lung cancer/mesothelial cell co-culture experiments. The ferroptosis resistance that protected cancer from death which was secondary to extracellular matrix detachment was critical for pleural metastasis. We found a universal presence of immune-suppressive lipid-associated tumor-associated macrophages (LA-TAMs) with complement cascade alteration in the MPE of the lung cancer patients. Specifically, upregulated complement factors were also found in the MPE, and C5 was associated with poor overall survival in the lung cancer patients with epidermal growth factor receptor mutation. Plasmacytoid dendritic cells (pDCs) exhibited a dysfunctional phenotype and pro-tumorigenic feature in the primary cancer. High expression of the gene set extracted from pDCs was associated with a poor prognosis in the lung cancer patients. Receptor-ligand interaction analysis revealed that the pleural metastatic niche was aggravated by cross-talk between mesothelial cells-cancer cells/immune cells via TNC and ICAM1 . Conclusions: Taken together, our results highlight cell-specific mechanisms involved in the pathobiological development of pleural metastasis in lung cancer. These results provide a large-scale and high-dimensional characterization of the pleural microenvironment and offer a useful resource for the future development of therapeutic drugs in lung cancer., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

The market for orthopedic implant alloys has seen significant growth in recent years, and efforts to reduce the carbon footprint of medical treatment (i.e., green medicine) have prompted extensive research on biodegradable magnesium-based alloys. Magnesium alloys provide the mechanical strength and biocompatibility required of medical implants; however, they are highly prone to corrosion. In this study, Mg-9Li alloy was immersed in cell culture medium to simulate degradation in the human body, while monitoring the corresponding effects of the reaction products on cells. Variations in pH revealed the generation of hydroxyl groups, which led to cell death. At day-5 of the reaction, a coating of MgCO 3 (H 2 O) 3 , HA, and α -TCP appeared on sample surfaces. The coating presented three-dimensional surface structures (at nanometer to submicron scales), anti-corrosion effects, and an altered surface micro-environment conducive to the adhesion of osteoblasts. This analysis based on bio-simulation immersion has important implications for the clinical use of Mg alloys to secure regenerated periodontal tissue., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wang, Hung, Uan, Fang, Kuo, Chang, Ohiro and Sun.)

Real-world data regarding the T790M mutation rate after acquiring resistance to first-line combination therapy with epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) and bevacizumab in patients with advanced non-small-cell lung cancer (NSCLC) are limited. The present study was aimed at analyzing predictors of acquired T790M mutations in this patient group. A total of 107 patients who received first-line combination therapy with EGFR-TKIs and bevacizumab at 11 tertiary referral centers in Taiwan were enrolled in this multicenter retrospective study. Survival data and genomic test results after acquiring resistance were analyzed. We discovered that patients who received a combination of afatinib, a second generation EGFR-TKI, and bevacizumab showed better progression-free survival (PFS). After disease progression, 59 patients (55.1%) were confirmed to test positive for EGFR T790M. A longer duration of first-line therapy could be a predictor of subsequent T790M mutations. To our knowledge, this is one of the few and early studies to demonstrate the T790M mutation rate after first-line combination therapy with an EGFR-TKI and bevacizumab. Whether the longer PFS afforded by the addition of bevacizumab could lead to subsequent T790M mutations needs further investigation., Competing Interests: CS-K received speaker honoraria from AstraZeneca, Boehringer Ingelheim, Roche, Pfizer, Eli Lilliy, Novartis, OnO Pharma, Chugai, Merck and Guardant Health. CS-K provided consultation for AstraZeneca, Boehringer Ingelheim, Eli Lilliy, Merck, Chugai, Takeda and Novartis. C-L C had received honoraria from AstraZeneca, Boehringer Ingelheim, Pfizer, and Roche. C-C H received honoraria from Boehringer Ingelheim, AstraZeneca, Eli Lilly, Roche/Genentech/Chugai, MSD, Merck, Pfizer, Novartis, Takeda, BMS and Ono pharmaceutical, Merck, Pfizer, Novartis, Takeda. J-Y H received honoraria from Boehringer Ingelheim, AstraZeneca, Eli Lilly, Roche/Genentech/Chugai, MSD, Merck, Pfizer, Novartis, Takeda, BMS and Ono pharmaceutical, Merck, Pfizer, Novartis, Takeda., (AJCR Copyright © 2023.)

Laparoscopic (LPD) and robotic pancreaticoduodenectomy (RPD) are both challenging procedures. The feasibility and safety of simultaneously developing LPD and RPD remain unreported. We retrospectively reviewed the data of patients undergoing LPD or RPD between 2014 and 2021. A total of 114 patients underwent minimally invasive pancreaticoduodenectomy (MIPD): 39 LPDs and 75 RPDs. The learning process of LPD and RPD were similar. The cutoff points of the learning curve were LPD, 13th patient (the 27th patient of MIPD), and RPD, 18th patient (the 31st patient of MIPD) according the cumulative sum analysis of operative time. A decrease in the operative time was associated with the case sequence (p < 0.001) but not with the surgical approach (p = 0.36). The overall surgical outcomes were comparable between both the LPD and RPD groups. When evaluating the learning curve impact on MIPD, LPD had higher major complication (≧ Clavien-Dindo grade III), bile leak and wound infection rates in the pre-learning curve phase than those in the after-learning curve phase, while RPD had similar surgical outcomes between two phases. Simultaneous development of LPD and RPD is feasible and safe for experienced surgeons, with similar learning process and comparable surgical outcomes., (© 2023. The Author(s).)

Afatinib is an irreversible tyrosine kinase inhibitor (TKI) targeting the epidermal growth factor receptor (EGFR), which is utilized for the treatment of patients with advanced lung cancer that harbors EGFR mutations. No studies have evaluated the clinical efficacy of LCT in patients treated with first-line afatinib. In this study, we retrospectively enrolled patients with advanced lung adenocarcinomas harboring susceptible EGFR mutations who were diagnosed and treated with first-line afatinib in three hospitals. A total of 254 patients were enrolled, including 30 (12%) patients who received LCT (15 patients received definitive radiotherapy for the primary lung mass and 15 patients received curative surgery). Patients who received LCT had a significantly longer PFS than those who did not (median PFS: 32.8 vs. 14.5 months, p = 0.0008). Patients who received LCT had significantly longer OS than those who did not (median OS: 67.1 vs. 34.5 months, p = 0.0011). Multivariable analysis showed LCT was an independent prognostic factor for improved PFS (adjusted hazard ratio [aHR] [95% confidence interval (CI)]: 0.44 [0.26-0.73], p = 0.0016) and OS (aHR [95% CI]: 0.26 [0.12-0.54], p = 0.0004). The analyses using propensity score-weighting showed consistent results. We conclude that LCT may improve clinical outcomes, in terms of PFS and OS, in patients with advanced EGFR -mutant lung adenocarcinomas who are treated with first-line afatinib., Competing Interests: The authors declare no conflict of interest related to this article.

Background: The poor outcome of patients with lung squamous cell carcinoma (LUSC) highlights the importance of the identification of novel effective prognostic markers and therapeutic targets. Long noncoding RNAs (lncRNAs) have generally been considered to serve important roles in tumorigenesis and the development of various types of cancer, including LUSC., Methods: Here, we aimed to investigate the role of LINC02323 in LUSC and its potential mechanisms by performing comprehensive bioinformatic analyses., Results: LINC02323 was elevated and positively associated with unfavorable prognosis of LUSC patients. LINC02323 exerted oncogenic function by competitively binding to miR-1343-3p and miR-6783-3p, thereby upregulating L1CAM expression. Indeed, we also determined that LINC02323 could interact with the RNA-binding protein DDX3X, which regulates various stages of RNA expression and processing., Conclusion: Taken together, we identified that LINC02323 and its indirect target L1CAM can act as novel biomarkers for determining the prognosis of patients with LUSC and thus deserves further study., (© 2022 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Brain metastasis in patients with non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations is a factor of poor prognosis. We conducted a retrospective study to determine the optimal treatment strategy for EGFR-mutant NSCLC patients with brain metastasis receiving or not receiving intracranial intervention. A total of 186 patients treated with an EGFR TKI were enrolled in the study, and 79 (42%) received intracranial intervention. Patients who received intracranial intervention and those who did not had a similar treatment response rate (RR), progression-free survival (PFS) (median PFS: 11.0 vs. 10.0 months, p = 0.4842), and overall survival (OS) (median OS: 23.0 vs. 23.2 months, p = 0.2484). Patients treated with gefitinib, erlotinib, afatinib, or osimertinib had a similar RR (63%, 76%, 81%, or 100%, respectively, p = 0.1390), but they had significantly different PFS (median PFS: 7.5, 10.0, 14.8 months, or not reached, respectively, p = 0.0081). In addition, OS tended to be different between different EGFR TKI treatments (median OS of 19.2, 23.7, or 33.0 months for gefitinib, erlotinib, or afatinib treatments, respectively, p = 0.0834). Afatinib and osimertinib both demonstrated significantly longer PFS than gefitinib in a Cox regression model. Graded prognostic assessment (GPA) versions 2017 and 2022 stratified patients with different OS; patients with higher GPA index scores had significantly longer OS ( p = 0.0368 and 0.0407 for version 2017 and 2022, respectively).

Lung squamous cell carcinoma (LUSC) represents a minor proportion of nonsmall cell lung cancer (NSCLC) harboring a poor prognosis. Herein, retrospective medical record research was performed to investigate real-world treatment patterns and identify the prognostic factors among LUSC patients. A total of 173 patients with a median age of 68 years were enrolled for analysis. Males were predominant (n = 143, 83%) and current or ex-smokers contributed to 78% of the entire cohort. Pleura and lung were the most common metastatic sites, whereas brain metastasis was only 7%. After diagnosis, however, only 107 patients (62%) had received first-line chemotherapy. In the chemotherapy cohort, median progression-free survival (PFS) and overall survival (OS) were 3.9 and 11.1 months, respectively. After multivariable analysis, bone metastasis and the use of first-line single-agent chemotherapy independently predicted shorter PFS. For baseline characteristics, male sex, metastasis to lung, pleura, liver, and bone independently predicted worse OS. Regarding the treatment pattern, patients who had undergone standard first-line doublet therapy and employed targeted therapies after disease progression linked to longer OS. In the real world, even those who underwent chemotherapy still had poor outcome. The findings may help clinicians to orchestrate the treatment strategies for LUSC patients and provide further direction of large-scale studies., (© 2022 The Authors. The Kaohsiung Journal of Medical Sciences published by John Wiley & Sons Australia, Ltd on behalf of Kaohsiung Medical University.)

Immune checkpoint inhibitors (ICIs) are the standard treatment for non-small-cell lung cancer (NSCLC). We assessed the clinical prognostic factors in NSCLC patients receiving atezolizumab as a second- or later-line (2L+) treatment. Data were retrospectively collected for NSCLC patients treated with atezolizumab from July 2017 to June 2019 at six medical centers in Taiwan. Clinical characteristics, treatment course and responses of patients were recorded. A total of 128 NSCLC patients received 2L+ atezolizumab, and the outcomes included a response rate of 10.2%, median progression-free survival (mPFS) of 3.5 months, and median overall survival (mOS) of 10.7 months. Eleven patients who had received osimertinib treatment before atezolizumab had a shorter mPFS (2.3 versus 3.5 months; p = 0.002) and mOS (4.8 versus 11.2 months; p < 0.001) than those without prior osimertinib treatment. Even for the subgroup of patients with EGFR -mutant non-squamous NSCLC, prior osimertinib was still associated with shorter PFS (2.3 versus 4.1 months; p = 0.006) and OS (4.8 versus 11.7 months; p < 0.001). Multivariate analysis revealed that prior osimertinib treatment correlated with not only shorter PFS (hazard ratio [HR]: 2.94; 95% confidence interval [CI], 1.34-6.47; p = 0.007) but also shorter OS (HR, 3.55; 95% CI, 1.57-8.03; p = 0.002). Patients with prior ICIs treatment (HR, 3.18; p = 0.002) or poor performance status (HR, 2.70; p = 0.001) had shorter OS. In conclusion, osimertinib treatment before atezolizumab therapy was associated with a shorter PFS and a poor prognosis in NSCLC patients in real-world settings. Further studies with larger sample sizes are needed to validate these observations., Competing Interests: Competing Interests: The authors declare that this study received funding from F. Hoffmann-La Roche, Ltd. The funder was not involved in the study design, patient collection, data analysis, interpretation of data, or the decision to submit it for publication. All authors met the authorship criteria as recommended by the International Committee of Medical Journal Editors (ICMJE) and retained full control of the manuscript content. SG Wu has received speaking honoraria from Roche, AstraZeneca, and Pfizer. CL Chiang has received honoraria from AstraZeneca, Boehringer Ingelheim, and Roche. CH Kuo, CC Wang, and JY Hung declare no conflict of interest. TC Hsia has received research grants from Eli Lilly. JY Shih has received personal fees for advisory boards from AstraZeneca, Roche, Boehringer Ingelheim, Eli Lilly, Merck Sharp & Dohme, Ono Pharmaceutical, Chugai Pharmaceutical, and Bristol-Myers Squibb; speaking honoraria from AstraZeneca, Roche, Boehringer Ingelheim, Eli Lilly, Pfizer, Novartis, Merck Sharp & Dohme, Ono Pharmaceutical, Chugai Pharmaceutical, and Bristol-Myers Squibb; and travel expense from Roche, Pfizer, Merck Sharp & Dohme, Chugai Pharmaceutical, and Bristol-Myers Squibb., (© The author(s).)

Lung adenocarcinoma (LUAD) is a common type of lung cancer. Although the diagnosis and treatment of LUAD have significantly improved in recent decades, the survival for advanced LUAD is still poor. It is necessary to identify more targets for developing potential agents against LUAD. This study explored the dysregulation of translation initiation factors, specifically eukaryotic initiation factors 4A1 ( EIF4A1 ) and EIF4A2 , in developing LUAD, as well as their underlying mechanisms. We found that the expression of EIF4A1 , but not EIF4A2 , was higher in tumor tissue and associated with poor clinical outcomes in LUAD patients. Elevated expression of EIF4H with poor prognosis may potentiate the oncogenic role of EIF4A1 . Functional enrichment analysis revealed that upregulation of EIF4A1 was related to cell cycle regulation and DNA repair. The oncogenic effect of EIF4A1 was further elucidated by Gene Set Variation Analysis (GSVA). The GSVA score of the gene set positively correlated with EIF4A1 was higher in tumors and significantly associated with worse survival. In the meantime, gene set enrichment analysis (GSEA) also indicated that elevated EIF4A1 expression in LUAD patients was associated with a decreased infiltration score for immune cells by reducing anticancer immune cell types and recruiting immunosuppressive cells. Consistent with the results, the GSVA score of genes whose expression was negatively correlated with EIF4A1 was lower in the tumor tissue of LUAD cases with worse clinical outcomes and was strongly associated with the disequilibrium of anti-cancer immunity by recruiting anticancer immune cells. Based on the results from the present study, we hypothesize that the dysregulation of EIF4A1 might be involved in the pathophysiology of LUAD development by promoting cancer growth and changing the tumor immune microenvironment. This can be used to develop potential diagnostic biomarkers or therapeutic targets for LUAD.

Patients with advanced non-small cell lung cancer (NSCLC) who harbor susceptible epidermal growth factor receptor (EGFR) mutations and are treated with EGFR tyrosine kinase inhibitors (TKIs) show longer progression-free survival (PFS) than those treated with chemotherapy. However, developed EGFR-TKI resistance limits PFS improvements. Currently, combination treatment with EGFR-TKIs and anti-angiogenic agents is considered a beneficial regimen for advanced-stage NSCLC harboring susceptible EGFR mutations. However, several trials reported osimertinib plus bevacizumab failed to show superior efficacy over osimertinib alone. However, subgroup analysis showed significantly longer PFS among patients with a history of smoking over those who never smoked. We performed a comprehensive systematic review and meta-analysis to evaluate the smoking status impact. At the end of the process, a total of 2068 patients from 11 randomized controlled trials (RCTs) were included in our meta-analysis. Overall, combination EGFR-TKI plus anti-angiogenic agent treatment showed significantly better PFS among patients with a smoking history (Hazard Ratio (HR) = 0.59, 95% confidence interval (CI) = 0.48-0.73). Erlotinib-based combination therapy showed positive PFS benefits regardless of smoking status (HR = 0.54, 95%CI = 0.41-0.71 for ever smoker, HR = 0.69, 95%CI = 0.54-0.87 for never smoker). Combination therapy prolonged PFS significantly regardless of ethnicity (HR: 0.64, 95% CI: 0.44-0.93 for Asian RCTs, HR: 0.55, 95% CI: 0.41-0.74 for global and non-Asian RCTs). PROSPERO registration number is CRD42022304198).

To assess the feasibility of dynamic hybrid-phase computed tomography (CT DHP ) simulation when patients undergo lung stereotactic body radiation therapy (SBRT). Eighteen non-small-cell lung-cancer patients were immobilised in a stereotactic body frame with abdominal compression. All underwent dynamic hybrid-phase CT scans that were compared with cone-beam CT (CBCT). We also determined the internal target volume (ITV) and evaluated the following four metrics: the "AND" function in the Boolean module of Eclipse, volume overlap (VO), Dice similarity coefficient (DSC), and dose-volume histogram. The average ITV values of 4DCT DHP and 3D-CBCT were respectively 12.82±10.42 and 14.6±12.18 cm 3 (n=72, p<0.001), and the average ITV value of AND was 11.7±10.1 cm 3 . The average planning target volume (PTV) of 4DCT DHP and 3D-CBCT was 25.63±18.04 and 28.00±19.82 cm 3 (n=72, p<0.001). The median AND difference between ITV and PTV was significant (p<0.01) and had a significantly linear distribution (R 2 =0.991 for ITV, R 2 =0.972 for PTV). The average VO of PTV was greater than that of ITV (0.81±0.096; 0.78±0.11). We also observed that the average DSC in PTV (0.83±0.066) was greater than that in ITV (0.81±0.084). The average results indicated that 97.9%±3.44 of ITV CBCT was covered by 95% of the prescribed dose. The average minimum, maximum and mean percentage doses of ITV CBCT were 87.9%±9.46, 107.3%±1.57, and 101.3%±1.12, respectively. This paper has demonstrated that dynamic hybrid-phase CT simulation for patients undergoing lung SBRT and also published evaluation metrics in scientific analysis. Our approach also has the advantage of adequate margin and fewer phases in CT simulation., (Copyright © 2021 American Association of Medical Dosimetrists. Published by Elsevier Inc. All rights reserved.)

Lung cancer is well known for its high mortality worldwide. The treatment for advanced lung cancer needs more attention to improve its survival time. A disintegrin and metallopeptidase with thrombospondin motifs 8 (ADAMTS8) has been linked to several cancer types. However, its role in lung cancer is worthy of deep investigation to promote novel drug development. This study took advantage of RNA-seq and bioinformatics to verify the role that ADAMTS8 plays in lung cancer. The functional assays suggested that ADAMTS8 mediates invasion and metastasis when expressed at a low level, contributing to poor overall survival (OS). The expression of ADAMTS8 was under the regulation of GATA Binding Protein 1 (GATA1) and executed its pathologic role through Thrombospondin Type 1 Domain Containing 1 (THSD1) and ADAMTS Like 2 (ADAMTSL2). To define the impact of ADAMTS8 in the lung cancer treatment strategy, this study further grouped lung cancer patients in the TCGA database into mutated epidermal growth factor receptor (EGFR)/wild-type EGFR and programmed death ligand 1 (PD-L1) high/low groups. Importantly, the expression of ADAMTS8 was correlated positively with the recruitment of anticancer NKT cells and negatively with the infiltration of immunosuppressive Treg and exhausted T cells. The results indicated that lung cancer patients with higher ADAMTS8 levels among wild-type EGFR or low PD-L1 groups survive longer than those with lower levels do. This study indicates that ADAMTS8 might be a treatment option for patients with lung adenocarcinoma who lack efficient targeted or immunotherapies.

Lung adenocarcinoma (LUAD) still holds the most dreadful clinical outcomes worldwide. Despite advanced treatment strategies, there are still some unmet needs. Next-generation sequencing of large-scale cancer genomics discovery projects combined with bioinformatics provides the opportunity to take a step forward in meeting clinical conditions. Based on in-house and The Cancer Genome Atlas (TCGA) cohorts, the results showed decreased levels of ADAMTS1 conferred poor survival compared with normal parts. Gene set enrichment analyses (GSEA) indicated the negative correlation between ADAMTS1 and the potential roles of epithelial-mesenchymal transition (EMT), metastasis, and poor prognosis in LUAD patients. With the knockdown of ADAMTS1, A549 lung cancer cells exhibited more aggressive behaviors such as EMT and increased migration, resulting in cancer metastasis in a mouse model. The pathway interaction network disclosed the linkage of downregulated α2-macroglobulin (A2M), which regulates EMT and metastasis. Furthermore, immune components analysis indicated a positive relationship between ADAMTS1 and the infiltrating levels of multiple immune cells, especially anticancer CD4 + T cells in LUAD. Notably, ADAMTS1 expression was also inversely correlated with the accumulation of immunosuppressive myeloid-derived suppressor cells and regulatory T cells, implying the downregulated ADAMTS1 mediated immune adjustment to fit the tumor survival disadvantages in LUAD patients. In conclusion, our study indicates that ADAMTS1 interacts with A2M in regulating EMT and metastasis in LUAD. Additionally, ADAMTS1 contributes to poor prognosis and immune infiltration in LUAD patients.

Background: Survival analyses are heavily used to analyze data in which the time to event is of interest. The purpose of this paper is to introduce some fundamental concepts for survival analyses in medical studies., Methods: We comprehensively review current survival methodologies, such as the nonparametric Kaplan-Meier method used to estimate survival probability, the log-rank test, one of the most popular tests for comparing survival curves, and the Cox proportional hazard model, which is used for building the relationship between survival time and specific risk factors. More advanced methods, such as time-dependent receiver operating characteristic, restricted mean survival time, and time-dependent covariates are also introduced., Results: This tutorial is aimed toward covering the basics of survival analysis. We used a neurosurgical case series of surgically treated brain metastases from non-small cell lung cancer patients as an example. The survival time was defined from the date of craniotomy to the date of patient death., Conclusions: This work is an attempt to encourage more investigators/medical practitioners to use survival analyses appropriately in medical research. We highlight some statistical issues, make recommendations, and provide more advanced survival modeling in this aspect., (Copyright © 2021 Elsevier Inc. All rights reserved.)

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., (© The Author(s) 2022. Published by Oxford University Press.)

Study Objectives: The association between sleep apnea (SA) and cataract was confirmed in a comprehensive large-scale study. This study aimed to investigate whether SA was associated with increased risk of cataract., Methods: The 18-year nationwide retrospective population-based cohort study used data retrieved from the Taiwan National Health Insurance Database. We selected adult patients with a diagnosis of SA, based on diagnostic codes (suspected SA cohort) or on presence of diagnosis after polysomnography (SA cohort), and matched each of them to 5 randomly selected, and age- and sex-matched control participants. The incidence rate of cataract was compared between patients with SA and the controls. The effect of SA on incident cataract was assessed using multivariable Poisson regression and Cox regression analyses., Results: A total of 6,438 patients in the suspected SA cohort were matched with 32,190 controls (control A cohort), including 3,616 patients in the SA cohort matched with 18,080 controls (control B cohort). After adjusting for age, sex, residency, income level, and comorbidities, the incidence rates of cataract were significantly higher in the SA cohorts than in the corresponding control cohorts. SA was an independent risk factor for incident cataract (adjusted hazard ratio [95% confidence interval]: 1.4 [1.2-1.6]). In patients with SA, elder age, heart disease, chronic pulmonary disease, and diabetes mellitus were independent risk factors for incident cataract., Conclusions: Our study revealed a significantly higher risk for developing cataract in patients with SA. Physicians caring for patients with SA should be aware of this ophthalmic complication., Citation: Liu P-K, Chang Y-C, Wang N-K, et al. The association between cataract and sleep apnea: a nationwide population-based cohort study. J Clin Sleep Med . 2022;18(3):769-777., (© 2022 American Academy of Sleep Medicine.)

The aim of this study is to develop an AI model that accurately identifies referable blepharoptosis automatically and to compare the AI model's performance to a group of non-ophthalmic physicians. In total, 1000 retrospective single-eye images from tertiary oculoplastic clinics were labeled by three oculoplastic surgeons as having either ptosis, including true and pseudoptosis, or a healthy eyelid. A convolutional neural network (CNN) was trained for binary classification. The same dataset was used in testing three non-ophthalmic physicians. The CNN model achieved a sensitivity of 92% and a specificity of 88%, compared with the non-ophthalmic physician group, which achieved a mean sensitivity of 72% and a mean specificity of 82.67%. The AI model showed better performance than the non-ophthalmic physician group in identifying referable blepharoptosis, including true and pseudoptosis, correctly. Therefore, artificial intelligence-aided tools have the potential to assist in the diagnosis and referral of blepharoptosis for general practitioners.

Background and Aims: Scarce data are available on in-hospital hepatitis C virus (HCV) micro-elimination strategies. This pilot study was prospectively conducted to assess the outcomes of HCV in-hospital micro-elimination program (HCV-HELP) in a single center in Taiwan., Methods: The study included the HCV reflex test for plans A (hospital personnel), B (outpatient surveillance), C (a call-back system for anti-HCV+ patients), and D (surveillance of cancer patients prior to chemotherapy). The primary outcome measurement was that > 80% of eligible patients were enrolled in linkage-to-treat; the secondary outcome measurement was the surveillance efficacy., Results: We recruited 930, 6072, 2376 and 233 participants into plans A, B, C, and D, respectively, from Oct 2020 to May 2021. The anti-HCV-seropositivity prevalences were 0.22% for plan A, 4.3% for B, and 3.9% for D. Two staff members were identified as HCV-viremic in plan A; these staff members successfully achieved a sustained virological response (SVR). We identified 39, 95 and 2 HCV-viremic patients in plans B, C, and D, respectively. Of these 138 HCV-viremic patients, 135 (97.8%) received direct-acting antiviral therapy, and 134 achieved SVR. Two 4-month phases were stratified to compare efficacies in the liver clinic. In the late phase, the adjusted number of HCV-viremic patients was 4.36/10,000 outpatient visits (90/200,689), which was 3.18-fold higher than that of the early phase (1.37/10,000 outpatient visits [30/212,658], odds ratio 3.18; 95% confidence interval 2.10-4.81, p < 0.0001)., Conclusion: HCV micro-elimination is achievable at the hospital level as per the structured HCV-HELP study., (© 2021. Asian Pacific Association for the Study of the Liver.)

Background/purpose: Three first-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are widely available to treat advanced lung adenocarcinoma harboring EGFR mutation. However, studies comparing efficacy or effectiveness of these EGFR TKIs came out with inconclusive results., Methods: In this real-world data analysis with a nationwide retrospective cohort design, adult patients with newly diagnosed advanced lung adenocarcinoma with EGFR mutation between 2011 and 2016, who received a first-line EGFR TKI, were included. Overall survival (OS) and time to next treatment (TTNT) were compared between patients receiving different EGFR TKIs after overlap weighting., Results: We enrolled 10,431 patients, including 6,230, 2,359, and 1842 in gefitinib, erlotinib, and afatinib groups, respectively. The median (95% confidence interval [CI]) OS were 24.2 (22.9-26.2), 25.7 (24.0-27.9), and 29.1 (25.8-32.1) months for those receiving gefitinib, erlotinib, and afatinib, respectively (p = 0.001). The hazard ratios (95% CI) for the afatinib group were 0.85 (0.74-0.98) and 0.91 (0.79-1.05) comparing with the gefitinib and erlotinib groups, respectively. The median (95% CI) TTNT were 10.9 (10.4-11.2), 11.7 (11.3-12.1), 13.4 (12.5-14.3) months for those receiving gefitinib, erlotinib, and afatinib, respectively (p < 0.001). The hazard ratios (95% CI) for the afatinib group were 0.79 (0.70-0.88) and 0.89 (0.79-1.00) comparing with the gefitinib and erlotinib groups, respectively. There were 6111 (59%) patients receiving subsequent therapies, and the majority of them received a second-line chemotherapy, particularly platinum-based chemotherapy., Conclusion: Afatinib, compared with gefitinib, might provide better effectiveness as the first-line targeted therapy for patients of advanced lung adenocarcinoma with EGFR mutation., Competing Interests: Declaration of competing interest LTC received honorariums from Eli Lilly, TTY Biopharm, Sanofi, SynCore Biotechnology, Astellas Pharma, PharmaEngine, and Ipsen, and also received study medications from TTY Biopharm, Syncore Biotechnology, and Celgene for other investigator-initiated trials. JYH received honorariums from Eli Lilly, Sanofi, Roche, AstraZeneca, Boehringer Ingelheim, Ono, and MSD. MJT received honorariums for lectures, which were not associated with this article, from AstraZeneca and Boehringer Ingelheim. The other authors have declared no conflicts of interest related to this article., (Copyright © 2021 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Patients with malignant pleural mesothelioma (MPM) have very poor prognoses, and pemetrexed plus platinum is the standard first-line therapy. However, the second-line therapy for relapsed MPM remains controversial. A comprehensive search was performed to identify randomized controlled trials (RCTs) evaluating various second-line regimens in patients with relapsed MPM. Indirect comparisons of overall survival (OS) and progression-free survival (PFS) were performed using network meta-analysis. Surface under the cumulative ranking curve (SUCRA) values were used to rank the included treatments according to each outcome. Nivolumab alone or nivolumab plus ipilimumab provided significantly longer OS than placebo (hazard ratio (HR): 0.72, 95% confidence interval (CI): 0.55-0.94 for nivolumab alone; HR: 0.54, 95% CI: 0.31-0.92 for nivolumab plus ipilimumab). The best SUCRA ranking for OS was identified for nivolumab plus ipilimumab (SUCRA: 90.8%). Tremelimumab, vorinostat, nivolumab alone, chemotherapy (CTX), asparagine-glycine-arginine-human tumor necrosis factor plus CTX, and nivolumab plus ipilimumab all produced noticeable PFS benefits compared with placebo. Nivolumab plus ipilimumab had the best PFS ranking (SUCRA: 92.3%). Second-line treatment with nivolumab plus ipilimumab provided the OS and PFS outcomes for patients with relapsed MPM.

Cancer remains a leading cause of death worldwide, despite many advances being made in recent decades. Changes in the tumor microenvironment, including dysregulated immunity, may contribute to carcinogenesis and cancer progression. The cysteinyl leukotriene (CysLT) pathway is involved in several signal pathways, having various functions in different tissues. We summarized major findings of studies about the roles of the CysLT pathway in cancer. Many in vitro studies suggested the roles of CysLTs in cell survival/proliferation via CysLT 1 receptor (CysLT 1 R). CysLT 1 R antagonism decreased cell vitality and induced cell death in several types of cancer cells, such as colorectal, urological, breast, lung and neurological malignancies. CysLTs were also associated with multidrug resistance of cancer, and CysLT 1 R antagonism might reverse chemoresistance. Some animal studies demonstrated the beneficial effects of CysLT 1 R antagonist in inhibiting tumorigenesis and progression of some cancer types, particularly colorectal cancer and lung cancer. The expression of CysLT 1 R was shown in various cancer tissues, particularly colorectal cancer and urological malignancies, and higher expression was associated with a poorer prognosis. The chemo-preventive effects of CysLT 1 R antagonists were demonstrated in two large retrospective cohort studies. In summary, the roles of the CysLT pathway in cancer have been delineated, whereas further studies are still warranted.

Natural killer (NKs) cells are cytotoxic effector cells, which can modulate tumor metastasis according to their function; however, the role of NK cells in lung cancer has not been extensively investigated. In this study, we determined the functional profiles of NK cells in a hypoxic tumor microenvironment (TME) of lung cancer. We revealed CD226 downregulation and functional repression of NK cells after hypoxic lung cancer priming and we then investigated their interaction with extracellular vesicles (EVs) and miR-150-5p. We also found that NK cells from lung cancer patients had lower expression of CD226 on their surface and exhibited a pro-inflammatory, pro-angiogenic and tumorigenesis phenotype by expressing VEGF, CXCL1, CXCL8, S100A8 and MMPs. Moreover, inhibition of miR-150 improved tumor surveillance by reversing CD226 expression and subsequently reinstating cytotoxic NK cell activity in an animal model. Our study introduces a new scenario for the pro-inflammatory and pro-angiogenic activities of NK cells in the hypoxic TME in lung cancer.

Smoking, sex, air pollution, lifestyle, and diet may act independently or in concert with each other to contribute to the different outcomes of lung cancer (LC). This study aims to explore their associations with the carcinogenesis of LC, which will be useful for formulating further preventive strategies. This retrospective, longitudinal follow-up cohort study was carried out by connecting to the MJ Health Database, Taiwan Cancer Registry database, and Taiwan cause of death database from 2000 to 2015. The studied subjects were persons attending the health check-ups, distributed throughout the main island of Taiwan. Cox proportional hazards regression models were used to investigate the risk factors associated with LC development and mortality after stratifying by smoking status, with a special emphasis on ambient two-year average PM 2.5 exposure, using a satellite-based spatiotemporal model at a resolution of 1 km 2 , and on dietary habit including consumption of fruits and vegetables. After a median follow-up of 12.3 years, 736 people developed LC, and 401 people died of LC-related causes. For never smokers, the risk of developing LC (aHR: 1.32, 95%CI: 1.12-1.56) and dying from LC-related causes (aHR: 1.28, 95%CI: 1.01-1.63) rises significantly with every 10 μg/m 3 increment of PM 2.5 exposure, but not for ever smokers. Daily consumption of more than two servings of vegetables and fruits is associated with lowering LC risk in ever smokers (aHR: 0.68, 95%CI: 0.47-0.97), and preventing PM 2.5 exposure is associated with lowering LC risk for never smokers.

Objectives: This study was conducted to explore the association between pneumoconiosis and pneumothorax., Design: Retrospective cohort study., Setting: Nationwide population-based study using the Taiwan National Health Insurance Database., Participants: A total of 2333 pneumoconiosis patients were identified (1935 patients for propensity score (PS)-matched cohort) and matched to 23 330 control subjects by age and sex (7740 subjects for PS-matched cohort)., Primary and Secondary Outcome Measures: The incidence and the cumulative incidence of pneumothorax., Results: Both incidence and the cumulative incidence of pneumothorax were significantly higher in the pneumoconiosis patients as compared with the control subjects (p<0.0001). For multivariable Cox regression analysis adjusted for age, sex, residency, income level and other comorbidities, patients with pneumoconiosis exhibited a significantly higher risk of pneumothorax than those without pneumoconiosis (HR 3.05, 95% CI 2.18 to 4.28, p<0.0001). The male sex, heart disease, peripheral vascular disease, chronic pulmonary disease and connective tissue disease were risk factors for developing pneumothorax in pneumoconiosis patients., Conclusions: Our study revealed a higher risk of pneumothorax in pneumoconiosis patients and suggested potential risk factors in these patients. Clinicians should be aware about the risk of pneumothorax in pneumoconiosis patients., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib are approved for advanced non-small-cell lung cancer (NSCLC) with ALK rearrangement. However, the mechanisms of resistance remain largely unclear., Methods: This prospective multicenter study analyzed cell-free DNA (cfDNA) and/or cancer tissues of patients with NSCLC after progression on ALK TKI(s), using targeted next-generation sequencing. Patients' clinicopathologic characteristics and treatment outcomes were analyzed., Results: Overall, 88 patients were enrolled; 31 cancer tissues and 90 cfDNA samples were analyzed. Five (16%) ALK mutations (L1196M ×2, I1171T, D1203N, G1269A/F1174L) and 3 possible bypass mutations (NRAS G12V, EGFR R108K, PIK3CA E545K) were found in 32 crizotinib-resistant cancers. Four (22%) ALK mutations (G1128A, G1202R, G1269A, I1171T/E1210K) and 3 possible bypass mutations (KIT D820E, MET E1012∗, EGFR P265&#95;C291del) were found in 18 ceritinib-resistant cancers. Four (17%) ALK mutations (G1202R ×2, W1295C, G1202R/L1196M) and 1 possible bypass mutation (EGFR P753S) were found in 24 alectinib-resistant cancers. Two (11%) ALK mutations (G1202R/G1269A ×2) and 2 possible bypass mutations (BRAF V600E, MET D1246N) were found in 18 lorlatinib-resistant cancers. In patients with simultaneous paired tissue and cfDNA samples (n = 20), mutations were identified in 9 (45%) and 6 (30%) cases, respectively; the concordance rate was 45%., Conclusions: The mechanisms of ALK TKI resistance were heterogeneous; ALK mutations were found in less than one-third of patients. Compound ALK mutations, which may confer lorlatinib resistance, may occur in crizotinib, ceritinib, and alectinib-resistant lung cancers., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: YTL has received speaking honoraria from ACT Genomics, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai Pharmaceutical, Manudipharma, Merck Sharp & Dohme, Novartis, Pfizer, Roche, and TTY Biopharm; and travel expense from Pfizer. CLC has received speaking honoraria from Chugai Pharmaceutical, Novartis, and Pfizer. SYW has received speaking honoraria from Boehringer Ingelheim, Merck Sharp & Dohme, Merck KGaA, Novartis, and Sanofi; and travel expense from Bristol-Myers Squibb and TTY Biopharm. HPC has received speaking honoraria from AstraZeneca, Chugai Pharmaceutical, Novartis, and Pfizer. CHC has received honoraria from AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Chugai Pharmaceutical, Eli Lilly, Merck Sharp & Dohme, Novartis, Ono Pharmaceutical, Pfizer, Roche, and Takeda. JYS has been an advisory board member for AstraZeneca, Roche, Boehringer Ingelheim, Eli Lilly, Merck Sharp & Dohme, Ono Pharmaceutical, Chugai Pharmaceutical, Bristol-Myers Squibb, Cstone Pharmaceuticals, Janssen Pharmaceutica, and Takeda. JYS has received speaking honoraria from AstraZeneca, Roche, Boehringer-Ingelheim, Eli Lilly, Pfizer, Novartis, Merck Sharp & Dohme, Ono Pharmaceutical, Chugai Pharmaceutical, and Bristol-Myers Squibb; and travel expense from Roche, Boehringer Ingelheim, Pfizer, Merck Sharp & Dohme, Chugai Pharmaceutical, and Bristol-Myers Squibb. The remaining authors declare no conflict of interest. Results from this study were presented, in part, at the 2020 Annual Congress of Taiwan Society of Pulmonary and Critical Care Medicine in Taipei, Taiwan, December 12, 2020., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Various anaplastic lymphoma kinase inhibitors (ALKIs) have been approved for first-line use in treating anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC). To date, no head-to-head comparison of these newer generation ALKIs has been made, and different efficacies of ALKIs may present across ethnicity. This study aims to compare newer generation ALKIs for treatment efficacy in Asian groups using network meta-analysis. Phase II/III trials that enrolled treatment-naïve Asian ALK-rearranged NSCLC patients treated by ALKIs were included. Progression-free survival (PFS) and overall response rate (ORR) of each trial were extracted as indicators of drug efficacy. Surfaces under cumulative ranking curves (SUCRAs) were calculated as a numeric presentation of the overall ranking associated with each agent. After a systematic literature review, six phase III clinical trials were included. Our results showed that newer generation ALKIs, such as alectinib, brigatinib, ensartinib, and lorlatinib, all demonstrated superior efficacy to crizotinib. Among those, ensartinib exhibited the best overall SUCRA value and ranked first among all agents. According to our network meta-analysis, ensartinib may currently be the most effective first-line treatment for Asian patients with ALK-positive NSCLC. However, this conclusion needs further validation by a larger scale of clinical trials or posthoc analysis of Asian populations. Moreover, in our comparison, low-dose alectinib (300 mg twice daily) exhibited an efficacy profile similar to a higher dose regimen in Asian populations.

Lung cancer remains notorious for its poor prognosis. Despite the advent of tyrosine kinase inhibitors and immune checkpoint inhibitors, the probability of curing the disease in lung cancer patients remains low. Novel mechanisms and treatment strategies are needed to provide hope to patients. Advanced strategies of next generation sequencing (NGS) and bioinformatics were used to analyze normal and lung cancer tissues from lung cancer patients. Amine oxidases have been linked to leukocyte migration and tumorigenesis. However, the roles of amine oxidases in lung cancer are not well‑understood. Our results indicated that amine oxidase, copper containing 3 (AOC3) was significantly decreased in the tumor tissue compared with the normal tissue, at both the mRNA and protein level, in the included lung cancer patients and public databases. Lower expression of AOC3 conferred a poorer survival probability across the different cohorts. Epigenetic silencing of AOC3 via miR‑3691‑5p caused tumor promotion and progression by increasing migration and epithelial‑mesenchymal transition (EMT). Furthermore, knockdown of AOC3 caused less CD4 + T‑cell attachment onto lung cancer cells and reduced transendothelial migration in vitro , as well as reducing CD4 + T‑cell trafficking to the lung in vivo . In conclusion, the present study revealed that downregulation of AOC3 mediated lung cancer promotion and progression, as well as decrease of immune cell recruitment. This novel finding could expand our understanding of the dysregulation of the tumor immune microenvironment and could help to develop a novel strategy for the treatment of lung cancer.

Introduction: Rovalpituzumab tesirine (Rova-T) is an antibody-drug conjugate targeting DLL3, an atypical Notch ligand expressed in SCLC tumors. We evaluated the efficacy of Rova-T versus placebo as maintenance therapy in patients with extensive-stage-SCLC after platinum-based chemotherapy., Methods: MERU was a phase 3 randomized, double-blinded, placebo-controlled study. Patients without disease progression after four cycles of platinum-based, front-line chemotherapy were randomized in a 1:1 ratio to receive 0.3 mg/kg Rova-T or placebo (every 6 wk, omitted every third cycle). Primary efficacy end points were progression-free survival (PFS) evaluated by the Central Radiographic Assessment Committee and overall survival (OS) in patients with DLL3-high tumors., Results: Median age of all randomized patients (N = 748) was 64 years; 78% had TNM stage IV disease. At futility analysis of the subset with DLL3-high tumors, the hazard ratio for OS was 1.07 (95% confidence interval: 0.84-1.36) favoring the placebo arm, with median OS of 8.5 and 9.8 months in the Rova-T and placebo arms, respectively; futility criteria were met. Rova-T significantly improved PFS versus placebo by investigator assessment (4.0 versus 1.4 mo, hazard ratio = 0.48, p < 0.001). Any-grade adverse events (≥20%) in the Rova-T arm were pleural effusion (27%), decreased appetite (27%), peripheral edema (26%), photosensitivity reaction (25%), fatigue (25%), nausea (22%), and dyspnea (21%)., Conclusions: Because of the lack of survival benefit in the Rova-T arm, the study did not meet its primary end point and was terminated early. As a result, the Central Radiographic Assessment Committee evaluation of PFS was not performed. The frequency of grade greater than or equal to 3 and drug-related toxicities were higher with Rova-T versus placebo. Rova-T was associated with unique toxicities, such as pleural and pericardial effusions, photosensitivity reaction, and peripheral edema, which should be carefully considered in the population with extensive-stage-SCLC., (Copyright © 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: Angiogenesis is required for tumor development and metastasis, which is a major part in a pro-tumor microenvironment. Vascular mimicry (VM) is a process in which cancer cells, rather than endothelia, create an alternative perfusion system to support the tumor progression., Objectives: To validate the role of VM and to develop a strategy to inhibit angiogenesis in lung cancer., Methods: In this study, we utilized lung cancer samples to verify the existence of VM and conducted several experimental methods to elucidate the molecular pathways., Results: H1299 and CL1-0 lung cancer cells were unable to form capillary-like structures. VM formation was induced by cancer-associated fibroblast (CAFs) in both in vitro and in vivo experiments. Notch2-Jagged1 cell-cell contact between cancer cells and CAFs contributes to the formation of VM networks, supported by Notch intracellular domain (NICD) 2 nuclear translocation and N2ICD target gene upregulated in lung cancer cells mixed with CAFs. The polarization of tumor-promoting N2-type neutrophil was increased by VM networks consisting of CAF and cancer cells. The intravasation of cancer cells and N2-type neutrophils were increased because of the loose junctions of VM. Disruption of cancer cell-CAF connections by a γ-secretase inhibitor enforced the anticancer effect of anti-vascular endothelial growth factor antibodies in a mouse model., Conclusion: This study provides the first evidence that CAFs induce lung cancer to create vascular-like networks. These findings suggest a therapeutic opportunity for improving antiangiogenesis therapy in lung cancer., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Tsai, Wu, Liu, Chang, Huang, Chang, Tsai, Liao, Hung and Hsu.)

Lung cancer has been a leading cause of cancer-related death for decades and therapeutic strategies for non-driver mutation lung cancer are still lacking. A novel approach for this type of lung cancer is an emergent requirement. Here we find that loss of LSAMP (Limbic System Associated Membrane Protein), compared to other IgLON family of proteins NTM (Neurotrimin) and OPCML (OPioid-binding Cell adhesion MoLecule), exhibits the strongest prognostic and therapeutic significance in predicting lung adenocarcinoma (LUAD) progression. Lower expression of LSAMP and NTM , but not OPCML , were found in tumor parts compared with normal parts in six LUAD patients, and this was validated by public datasets, Oncomine ® and TCGA. The lower expression of LSAMP , but not NTM , was correlated to shorter overall survival. Two epigenetic regulations, including hypermethylation and miR-143-3p upregulation but not copy number variation, were associated with downregulation of LSAMP in LUAD patients. Pathway network analysis showed that NEGR1 (Neuronal Growth Regulator 1) was involved in the regulatory loop of LSAMP. The biologic functions by LSMAP knockdown in lung cancer cells revealed LSMAP was linked to cancer cell migration via epithelial-mesenchymal transition (EMT) but not proliferation nor stemness of LUAD. Our result showed for the first time that LSAMP acts as a potential tumor suppressor in regulating lung cancer. A further deep investigation into the role of LSAMP in lung cancer tumorigenesis would provide therapeutic hope for such affected patients.

Background: The relative importance of predictive factors for advanced non-small cell lung cancer (NSCLC) patients on epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) treatment remains unclear., Materials and Methods: We retrospectively enrolled advanced NSCLC patients with single first-generation EGFR-TKI treatment for ⩾5 years (Y) in Taiwan. Clinical data was collected and compared with those of another cohort with single first-line EGFR-TKI treatment for <5 Y. Plasma cell-free DNA (cfDNA) samples were collected from patient subsets, pre- and post-TKI, in the >5 Y group., Results: Overall, 128 and 278 patients were enrolled in the ⩾5 Y and <5 Y groups, respectively. Significant factors in the multivariate analysis of patients' characteristics including Eastern Cooperative Oncology Group performance status 0-1, postoperative recurrence, without brain metastasis, oligometastasis (each score of 2), female sex, erlotinib use, and without bone metastasis (each score of 1), were incorporated into a risk scoring system. The area under the receiver operating characteristic curve was 0.82 [95% confidence interval (CI): 0.78-0.86]. Of the plasma cfDNA samples from 33 patients in the ⩾5 Y group, only 1 had a T790M in 25 patients without progressive disease. In 27 patients with single agent use for ⩾96 months, 22 (81.5%) received local treatment (surgery or radiotherapy) for the primary lung tumor before and during TKI treatment., Conclusion: For NSCLC patients with single first-generation EGFR-TKI use for ⩾5 Y, factors with different relative importance exist and the risk-scoring model is feasible with modest accuracy. The role of local treatment for primary tumors in patients with long-term TKI use requires further investigation., Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest., (© The Author(s), 2021.)

Background: Afatinib has shown favorable response rates (RRs) and longer progression free survival (PFS) in lung cancer patients harboring EGFR mutations compared with standard platinum-based chemotherapy. However, serious adverse drug reactions (ADRs) limit the clinical application of afatinib., Methods: We designed a retrospective study, enrolling all patients with metastatic lung adenocarcinoma who were diagnosed and treated with 30 or 40 mg daily afatinib as their initial treatment in three Kaohsiung Medical University-affiliated hospitals in Taiwan., Results: A total of 179 patients were enrolled in the study, of which 102 (57%) and 77 (43%) received 30 mg and 40 mg afatinib daily as their initial treatment, respectively. The patients initially using 30 mg afatinib daily had a similar RR (75% vs. 83%, p = 0.1672), median PFS (14.5 vs. 14.8 months, log-rank p = 0.4649), and median OS (34.0 vs. 25.2 months, log-rank p = 0.5982) compared with those initially using 40 mg afatinib daily. Patients initially receiving 30 mg afatinib daily had fewer ADRs compared with those using 40 mg daily. The overall incidence of moderate and severe ADRs was significantly lower in patients receiving 30 mg afatinib daily compared with those using 40 mg daily (49% vs. 77%, p = 0.002); similar findings was observed in terms of severe ADRs (7% vs. 24%, p < 0.0001)., Conclusion: Patients receiving 30 mg afatinib daily as their initial treatment had similar RR, PFS, OS, but significantly fewer serious ADRs, as compared with those using 40 mg as their starting dose.

The prognosis of patients with metastatic lung adenocarcinoma (LUAD) is poor. Although novel lung cancer treatments have been developed for metastatic LUAD, not all patients are fit to receive these treatments. The present study aimed to identify the novel regulatory genes in metastatic LUAD. Because the pleural cavity is a frequent metastasis site of LUAD, the adjacent non-tumor tissue, primary tumor tissue, and metastatic lung tumor tissue in the pleura of a single patient with LUAD were collected. The gene expression profiles of the collected samples were further analyzed via RNA sequencing and bioinformatic analysis. A high expression level of ubiquitin conjugating enzyme E2 H (UBE2H), a hypoxia-mediated gene, was identified in the metastatic malignant pleural tumor. After accessing the survival data in patients with lung adenocarcinoma through online databases, a high UBE2H expression was associated with poor survival for LUAD. UBE2H knockdown in two lung adenocarcinoma cell lines suppressed the cell migration capacity and reversed the epithelial-mesenchymal transition (EMT) signaling pathway. A high expression of UBE2H-targeting microRNAs, including miR-101, miR-30a, miR-30b, miR-328, and miR-497, were associated with a favorable prognosis. Moreover, the UBE2H expression revealed a significant correlation with the copy number variation. Taken together, the presence of UBE2H regulated the EMT program and metastasis in LUAD.