Assessing EGFR-mutated NSCLC with bone metastasis: Clinical features and optimal treatment strategy.

BACKGROUND: This study aimed to examine the clinical characteristics of bone metastasis (BoM) in patients with non-small cell lung cancer (NSCLC) who have an epidermal growth factor receptor (EGFR) mutation and to identify the most effective treatment strategy using EGFR-tyrosine kinase inhibitors (TKIs). METHODS: The study included patients with stage IV EGFR-mutated NSCLC who were receiving first-line treatment with EGFR-TKIs between January 2014 and December 2020. These patients were divided into two groups based on the presence or absence of BoM at the time of initial diagnosis. The BoM group was further subdivided based on whether they received denosumab or not. RESULTS: The final analysis included 247 patients. Those with BoM at initial diagnosis had shorter progression-free survival (12.6 vs. 10.5 months, p = 0.002) and overall survival (OS) (49.7 vs. 30.9 months, p = 0.002) compared to those without BoM. There was a difference in the location of metastatic sites between the two groups, with a higher incidence of extrathoracic metastasis in the BoM group (p < 0.001). The incidence of T790M was higher in patients with BoM than in those without (47.4% vs. 33.9%, p = 0.042). Multivariate Cox regression analysis revealed that sequential osimertinib treatment and the addition of antiangiogenic therapy (AAT) and denosumab therapy improved OS in patients with BoM. CONCLUSIONS: The presence of BoM is a negative prognostic factor for NSCLC patients with an EGFR mutation, possibly due to the presence of extrathoracic metastases. However, adding AAT and denosumab, along with sequential osimertinib, to the treatment regimen for patients with BoM can improve survival outcomes.

The difference between dacomitinib and afatinib in effectiveness and safety in first-line treatment of patients with advanced EGFR-mutant non-small cell lung cancer: a real-world observational study.

OBJECTIVES: The irreversible epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) afatinib and dacomitinib are approved for first-line treatment of EGFR mutation-positive non-small cell lung cancer (NSCLC). We aimed to compare the efficacy and safety of afatinib and dacomitinib in this setting. MATERIALS AND METHODS: Between September 2020 and March 2023, we retrospectively recruited patients diagnosed with advanced-stage EGFR-mutant NSCLC who were treated with first-line irreversible EGFR-TKIs. The enrolled patients were assigned to two groups based on whether they received afatinib or dacomitinib. RESULTS: A total of 101 patients were enrolled in the study (70 to afatinib and 31 to dacomitinib). The partial response rates (PR) for first-line treatment with afatinib and dacomitinib were 85.7 and 80.6% (p = 0.522). The median progression-free survival (PFS) (18.9 vs. 16.3 months, p = 0.975) and time to treatment failure (TTF) (22.7 vs. 15.9 months, p = 0.324) in patients with afatinib and dacomitinib treatment were similar. There was no significant difference observed in the median PFS (16.1 vs. 18.9 months, p = 0.361) and TTF (32.5 vs. 19.6 months, p = 0.182) between patients receiving the standard dose and those receiving the reduced dose. In terms of side effects, the incidence of diarrhea was higher in the afatinib group (75.8% vs. 35.5%, p < 0.001), while the incidence of paronychia was higher in the dacomitinib group (58.1% vs. 31.4%, p = 0.004). The PFS (17.6 vs. 24.9 months, p = 0.663) and TTF (21.3 vs. 25.1 months, p = 0.152) were similar between patients younger than 75 years and those older than 75 years. CONCLUSION: This study showed that afatinib and dacomitinib had similar effectiveness and safety profiles. However, they have slightly different side effects. Afatinib and dacomitinib can be safely administered to patients across different age groups with appropriate dose reductions.

iDVEIP: A computer-aided approach for the prediction of viral entry inhibitory peptides.

With the notable surge in therapeutic peptide development, various peptides have emerged as potential agents against virus-induced diseases. Viral entry inhibitory peptides (VEIPs), a subset of antiviral peptides (AVPs), offer a promising avenue as entry inhibitors (EIs) with distinct advantages over chemical counterparts. Despite this, a comprehensive analytical platform for characterizing these peptides and their effectiveness in blocking viral entry remains lacking. In this study, we introduce a groundbreaking in silico approach that leverages bioinformatics analysis and machine learning to characterize and identify novel VEIPs. Cross-validation results demonstrate the efficacy of a model combining sequence-based features in predicting VEIPs with high accuracy, validated through independent testing. Additionally, an EI type model has been developed to distinguish peptides specifically acting as Eis from AVPs with alternative activities. Notably, we present iDVEIP, a web-based tool accessible at http://mer.hc.mmh.org.tw/iDVEIP/, designed for automatic analysis and prediction of VEIPs. Emphasizing its capabilities, the tool facilitates comprehensive analyses of peptide characteristics, providing detailed amino acid composition data for each prediction. Furthermore, we showcase the tool's utility in identifying EIs against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2).

Single-Cell Secretion Analysis via Microfluidic Cell Membrane Immunosorbent Assay for Immune Profiling.

Single-cell multiplexed phenotypic analysis expands the biomarkers for diagnosis, heralding a new era of precision medicine. Cell secretions are the primary measures of immune function, but single-cell screening remains challenging. Here, a novel cell membrane-based assay was developed using cholesterol-linked antibodies (CLAbs), integrating immunosorbent assays and droplet microfluidics to develop a flexible high-throughput single-cell secretion assay for multiplexed phenotyping. CLAb-grafted single cells were encapsulated in water-in-oil droplets to capture their own secretions. Subsequently, the cells were extracted from droplets for fluorescence labeling and screening. Multiple secretions and surface proteins were simultaneously measured from single cells by flow cytometry. To validate the approach, THP-1 cells, THP-1-derived M1 macrophages, and dendritic cells were assayed, indicating the differentiation efficiency of THP-1 cells under different chemical stimulations. Moreover, peripheral blood mononuclear cells from healthy donors under various stimuli showed varied active immune cell populations (6.62-47.14%). The peripheral blood mononuclear cells (PBMCs) of nasopharyngeal carcinoma patients were analyzed to identify a higher percentage of actively cytokine-secreted single cells in the basal state (2.82 ± 1.48%), compared with that in the health donors (0.70 ± 0.29%).

A real-world study comparing perioperative chemotherapy and EGFR-tyrosine kinase inhibitors for treatment of resected stage III EGFR-mutant adenocarcinoma.

BACKGROUND: The patient population with stage III non-small-cell lung cancer (NSCLC) is heterogeneous, with varying staging characteristics and diverse treatment options. Despite the potential practice-changing implications of randomized controlled trials evaluating the efficacy of perioperative epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), concerns have been raised due to conflicting overall survival (OS) results. Few real-world studies have examined the survival outcomes of patients with resected EGFR-mutant stage III adenocarcinoma receiving perioperative chemotherapy and EGFR-TKIs. METHODS: In this retrospective observational study, we enrolled patients with resected stage III adenocarcinoma with EGFR mutations between January 2011 and December 2021. Patients were classified into two groups: perioperative chemotherapy and perioperative EGFR-TKIs. Outcomes and prognostic factors were analyzed using Cox proportional hazards regression analysis. RESULTS: Eighty-four patients were enrolled in the analysis. Perioperative EGFR-TKIs led to longer progression-free survival (PFS) than chemotherapy (38.6 versus 14.2 months; p = 0.019). However, only pathological risk factors predicted poor PFS in multivariate analysis. Patients receiving perioperative chemotherapy had longer OS than those receiving EGFR-TKIs (111.3 versus 50.2 months; p = 0.052). Multivariate analysis identified perioperative treatment with EGFR-TKIs as an independent predictor of poor OS (HR: 3.76; 95% CI: 1.22-11.54). CONCLUSION: Our study demonstrates that chemotherapy should be considered in the perioperative setting for high-risk patients, when taking pathological risk factors into consideration, and that optimized sequencing of EGFR-TKIs might be the most critical determinant of OS.

Evaluation of exogenous therapeutic protein activity under confinement and crowding effects.

Dysfunction of intracellular proteins is frequently associated with various diseases, such as cancer. The exogenous proteins in cells are usually assembled with specific configurations due to physiological confinement/crowding to exhibit novel features in the protein structure, folding or conformational stability, distinguished with their behaviors in buffer solutions. Here, we synthesized exogenous proteins under confined/crowded conditions, to explore protein activity within cells. The findings suggested that the confinement and crowding effects on protein activity are heterogeneous; they showed an inhibitory effect on HRP by decreasing Km from ∼9.5- and ∼21.7-fold and Vmax from ∼6.8- and ∼20.2-fold lower than that of dilute solutions. Interestingly, the effects on Cyt C seem to be more complicated, and crowding exerts a positive effect by increasing Km ∼ 3.6-fold and Vmax ∼ 1.5-fold higher than that of dilute solutions; however, confinement exhibits a negative effect by decreasing Km ∼2.0 and Vmax ∼8.3 times. Additionally, in contrast to traditional nanoparticle-based confinement models, we synthesized a biodegradable nanoparticle to mimic the confined space, and the biggest advantage of this novel model is that the particles can be degraded and thus it can provide more intuitive observations of the properties of the target proteins under confinement and after release. Furthermore, we also evaluated protein activity in different cellular environments, indicating that the exogenous protein activity was closely related to the crowdedness of cellular environments, and the inhibition of protein activity in MDA-MB-231 cancer cells was more obvious than in HEK293 normal cells. Finally, SAXS analysis revealed the correlation between the protein conformation and the different environments. Our work will provide a unique method for precisely assessing whether the target cellular environments are native matrix in which specific exogenous protein drugs are delivered to function or whether they display a therapeutic role, which is of great significance for screening and development of new drugs.

Highly Mimetic Ex Vivo Lung-Cancer Spheroid-Based Physiological Model for Clinical Precision Therapeutics.

Lung cancer remains a major health problem despite the considerable research into prevention and treatment methods. Through a deeper understanding of tumors, patient-specific ex vivo spheroid models with high specificity can be used to accurately investigate the cause, metastasis, and treatment strategies for lung cancer. Biofabricate lung tumors are presented, consisting of patient-derived tumor spheroids, endothelial cells, and lung decellularized extracellular matrix, which maintain a radial oxygen gradient, as well as biophysicochemical behaviors of the native tumors for precision medicine. It is also demonstrated that the developed lung-cancer spheroid model reproduces patient responses to chemotherapeutics and targeted therapy in a co-clinical trial, with 85% accuracy, 86.7% sensitivity, and 80% specificity. RNA sequencing analysis validates that the gene expression in the spheroids replicates that in the patient's primary tumor. This model can be used as an ex vivo predictive model for personalized cancer therapy and to improve the quality of clinical care.

Bevacizumab versus Ramucirumab in EGFR-Mutated Metastatic Non-Small-Cell Lung Cancer Patients: A Real-World Observational Study.

The combination of bevacizumab or ramucirumab with epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy, chemotherapy, or immunotherapy for non-small-cell lung cancer (NSCLC) patients with EGFR mutations could have survival benefits. However, no study, to date, has been conducted to compare the efficacy and safety of these two antiangiogenic therapies (AATs). Stage IIIB to IV EGFR-mutated NSCLC patients who received first-line EGFR-TKIs between January 2014 and May 2022 were enrolled. These patients were divided into two groups: those receiving bevacizumab and those receiving ramucirumab as a combination therapy in any line of treatment. Ninety-six patients were enrolled in this study's final analysis. The progression-free survival (PFS) of patients who received front-line AATs combined with EGFR-TKI therapy was longer than that of patients receiving later-line AATs combined with other therapies (19.6 vs. 10.0 months, p < 0.001). No difference in overall survival (OS) was observed between front-line and later-line therapy (non-reach vs. 44.0 months, p = 0.261). Patients who received these two different AATs did not differ in PFS (24.1 vs. 15.7 months, p = 0.454) and OS (48.6 vs. 43.0 months, p = 0.924). In addition, these two AATs showed similar frequencies of the T790M mutation (43.6% vs. 38.2%; p = 0.645). Multivariate Cox regression analysis indicated several AAT cycles as an independent good prognostic factor in OS. The incidence of some adverse events such as bleeding and hepatitis was higher for bevacizumab than for ramucirumab but it was not significant. Front-line AAT and EGFR-TKI combination therapy improved the PFS of stage IV EGFR-mutated NSCLC patients. The effectiveness and safety of the two AATs were similar.

A flexible liposomal polymer complex as a platform of specific and regulable immune regulation for individual cancer immunotherapy.

BACKGROUND: The applicability and therapeutic efficacy of specific personalized immunotherapy for cancer patients is limited by the genetic diversity of the host or the tumor. Side-effects such as immune-related adverse events (IRAEs) derived from the administration of immunotherapy have also been observed. Therefore, regulatory immunotherapy is required for cancer patients and should be developed. METHODS: The cationic lipo-PEG-PEI complex (LPPC) can stably and irreplaceably adsorb various proteins on its surface without covalent linkage, and the bound proteins maintain their original functions. In this study, LPPC was developed as an immunoregulatory platform for personalized immunotherapy for tumors to address the barriers related to the heterogenetic characteristics of MHC molecules or tumor associated antigens (TAAs) in the patient population. Here, the immune-suppressive and highly metastatic melanoma, B16F10 cells were used to examine the effects of this platform. Adsorption of anti-CD3 antibodies, HLA-A2/peptide, or dendritic cells' membrane proteins (MP) could flexibly provide pan-T-cell responses, specific Th1 responses, or specific Th1 and Th2 responses, depending on the host needs. Furthermore, with regulatory antibodies, the immuno-LPPC complex properly mediated immune responses by adsorbing positive or negative antibodies, such as anti-CD28 or anti-CTLA4 antibodies. RESULTS: The results clearly showed that treatment with LPPC/MP/CD28 complexes activated specific Th1 and Th2 responses, including cytokine release, CTL and prevented T-cell apoptosis. Moreover, LPPC/MP/CD28 complexes could eliminate metastatic B16F10 melanoma cells in the lung more efficiently than LPPC/MP. Interestingly, the melanoma resistance of mice treated with LPPC/MP/CD28 complexes would be reversed to susceptible after administration with LPPC/MP/CTLA4 complexes. NGS data revealed that LPPC/MP/CD28 complexes could enhance the gene expression of cytokine and chemokine pathways to strengthen immune activation than LPPC/MP, and that LPPC/MP/CTLA4 could abolish the LPPC/MP complex-mediated gene expression back to un-treatment. CONCLUSIONS: Overall, we proved a convenient and flexible immunotherapy platform for developing personalized cancer therapy.

Transdermal nanolipoplex simultaneously inhibits subcutaneous melanoma growth and suppresses systemically metastatic melanoma by activating host immunity.

Benefit for clinical melanoma treatments, the transdermal neoadjuvant therapy could reduce surgery region and increase immunotherapy efficacy. Using lipoplex (Lipo-PEG-PEI-complex, LPPC) encapsulated doxorubicin (DOX) and carrying CpG oligodeoxynucleotide; the transdermally administered nano-liposomal drug complex (LPPC-DOX-CpG) would have high cytotoxicity and immunostimulatory activity to suppress systemic metastasis of melanoma. LPPC-DOX-CpG dramatically suppressed subcutaneous melanoma growth by inducing tumor cell apoptosis and recruiting immune cells into the tumor area. Animal studies further showed that the colonization and growth of spontaneously metastatic melanoma cells in the liver and lung were suppressed by transdermal LPPC-DOX-CpG. Furthermore, NGS analysis revealed IFN-γ and NF-κB pathways were triggered to recruit and activate the antigen-presenting-cells and effecter cells, which could activate the anti-tumor responses as the major mechanism responsible for the therapeutic effect of LPPC-DOX-CpG. Finally, we have successfully proved transdermal LPPC-DOX-CpG as a promising penetrative carrier to activate systemic anti-tumor immunity against subcutaneous and metastatic tumor.

Anticancer peptide Q7 suppresses the growth and migration of human endometrial cancer by inhibiting DHCR24 expression and modulating the AKT-mediated pathway.

Endometrial cancer is one of the most common malignancy affecting women in developed countries. Resection uterus or lesion area is usually the first option for a simple and efficient therapy. Therefore, it is necessary to find a new therapeutic drug to reduce surgery areas to preserve fertility. Anticancer peptides (ACP) are bioactive amino acids with lower toxicity and higher specificity than chemical drugs. This study is to address an ACP, herein named Q7, which could downregulate 24-Dehydrocholesterol Reductase (DHCR24) to disrupt lipid rafts formation, and sequentially affect the AKT signal pathway of HEC-1-A cells to suppress their tumorigenicity such as proliferation and migration. Moreover, lipo-PEI-PEG-complex (LPPC) was used to enhance Q7 anticancer activity in vitro and efficiently show its effects on HEC-1-A cells. Furthermore, LPPC-Q7 exhibited a synergistic effect in combination with doxorubicin or paclitaxel. To summarize, Q7 was firstly proved to exhibit an anticancer effect on endometrial cancer cells and combined with LPPC efficiently improved the cytotoxicity of Q7.

Chondromalacia patella increases the risk of herpes zoster: a population-based study.

BACKGROUND: The reactivation of herpes zoster (HZ) is associated with disease stress. However, the relationship between chondromalacia patella (CMP) and HZ remains poorly understood. This study investigated the relationship between CMP and the risk of developing HZ. METHODS: Data were collected from the Taiwan's National Health Insurance Research Database. Patients with CMP diagnosed between 2000 and 2017 were assigned to the case group; patients without CMP were randomly selected from the same database and paired with controls matched by age and sex. The primary outcome was a diagnosis of HZ. All patients were followed until their diagnosis of HZ, their withdrawal from the NHI program, their death, or the end of 2017, whichever was earliest. The risk of developing HZ was compared between the case and control groups. RESULTS: In total, 22,710 patients with CMP and 90,840 matched controls were enrolled. The overall incidence rates of HZ in the CMP and control cohorts were 7.94 and 7.35 per 1,000 person-years, respectively. After potential confounders were controlled for, the case group exhibited a higher risk of HZ than did the control group [adjusted hazard ratio (aHR) = 1.06, p < 0.05]. In a stratification analysis by age, patients over 65 years old in the CMP group exhibited a higher risk of HZ than did those in the control group (aHR = 1.22, p < 0.01). In a stratification analysis by sex, women with CMP were at greater risk of developing HZ than women without CMP (aHR = 1.18, p < 0.01). CONCLUSION: Patients with CMP, especially elder adults and women, exhibited a higher risk of HZ. The HZ risk of patients with CMP should thus be assessed, and the necessity of HZ vaccination should be informed.

iDVIP: identification and characterization of viral integrase inhibitory peptides.

Antiretroviral peptides are a kind of bioactive peptides that present inhibitory activity against retroviruses through various mechanisms. Among them, viral integrase inhibitory peptides (VINIPs) are a class of antiretroviral peptides that have the ability to block the action of integrase proteins, which is essential for retroviral replication. As the number of experimentally verified bioactive peptides has increased significantly, the lack of in silico machine learning approaches can effectively predict the peptides with the integrase inhibitory activity. Here, we have developed the first prediction model for identifying the novel VINIPs using the sequence characteristics, and the hybrid feature set was considered to improve the predictive ability. The performance was evaluated by 5-fold cross-validation based on the training dataset, and the result indicates the proposed model is capable of predicting the VINIPs, with a sensitivity of 85.82%, a specificity of 88.81%, an accuracy of 88.37%, a balanced accuracy of 87.32% and a Matthews correlation coefficient value of 0.64. Most importantly, the model also consistently provides effective performance in independent testing. To sum up, we propose the first computational approach for identifying and characterizing the VINIPs, which can be considered novel antiretroviral therapy agents. Ultimately, to facilitate further research and development, iDVIP, an automatic computational tool that predicts the VINIPs has been developed, which is now freely available at http://mer.hc.mmh.org.tw/iDVIP/.

Photoelectrochemical degradation of trichloroethylene by iron modified TiO2 nanotube arrays.

In this study, iron was deposited to titanium dioxide nanotube arrays (TNAs) by impregnation method to enhance its photocatalytic ability. The as-synthesized iron-modified TNAs (Fe-TNAs) was employed in a photoelectrochemical (PEC) system to degrade trichloroethylene (TCE). Results of AFE-SEM analysis showed that the iron nanoparticles (NPs) were successfully attached evenly to the nozzle of Fe-TNAs. Results of XRD analysis confirmed the findings of EDS and XPS, indicating the success of iron modification. The absorption wavelength of Fe-TNAs-27 mL red-shifts to 543 nm which corresponds to the band gap of 2.54 eV after iron modification. Mott-Schottky analysis yielded a donor density of 7.21 × 1020 and 2.30 × 1020/cm3 for TNAs and Fe-TNAs-27 mL, respectively. The photo-generated electrons had a lifetime (τel) of 21.49 and 39.19 ms for TNAs and Fe-TNAs-27 mL, respectively, illustrating the reduce of recombination of photo-generated electron-hole pairs. process. PEC methods performed the most effective way to degrade TCE with a rate constant of 0.079 min-1 in Fe-TNAs PEC system. Mechanism of Fe-TNAs PEC system was proposed in detail.

Adenosine triphosphate-activated prodrug system for on-demand bacterial inactivation and wound disinfection.

The prodrug approach has emerged as a promising solution to combat bacterial resistance and enhance treatment efficacy against bacterial infections. Here, we report an adenosine triphosphate (ATP)-activated prodrug system for on-demand treatment of bacterial infection. The prodrug system benefits from the synergistic action of zeolitic imidazolate framework-8 and polyacrylamide hydrogel microsphere, which simultaneously transports indole-3-acetic acid and horseradish peroxidase in a single carrier while preventing the premature activation of indole-3-acetic acid. The ATP-responsive characteristic of zeolitic imidazolate framework-8 allows the prodrug system to be activated by the ATP secreted by bacteria to generate reactive oxygen species (ROS), displaying exceptional broad-spectrum antimicrobial ability. Upon disruption of the bacterial membrane by ROS, the leaked intracellular ATP from dead bacteria can accelerate the activation of the prodrug system to further enhance antibacterial efficiency. In vivo experiments in a mouse model demonstrates the applicability of the prodrug system for wound disinfection with minimal side effects.

When to add anti-angiogenesis drugs to EGFR-mutated metastatic non-small cell lung cancer patients: a real-world study from Taiwan.

BACKGROUND: The addition of anti-angiogenesis drugs to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) or chemotherapy in patients with EGFR-mutant non-small cell lung cancer (NSCLC) can improve disease control. We conducted a study to evaluate the efficacy of combination therapeutic strategies and identify patients who could benefit from combination therapy. METHODS: This study enrolled patients with stage IV EGFR-mutant NSCLC treated with first-line EGFR-TKIs between January 2014 and December 2020. We divided patients into three groups: patients who received an anti-angiogenesis drug as first-line combination therapy, those who received an anti-angiogenesis drug as further-line combination therapy, and those with no anti-angiogenesis therapy. RESULTS: A total of 204 patients were enrolled in the final analysis. Progression-free survival (PFS) in patients receiving first-line anti-angiogenesis plus EGFR-TKI combination therapy was longer (18.2 months) than those treated with first-line EGFR-TKI monotherapy (10.0 months for both, p < 0.001). No difference in overall survival (OS) was observed among these three groups (30.5 vs. 42.6 vs. 33.7 months, p = 0.326). Multivariate Cox regression analysis revealed L858R mutation, pleural, liver, and bone metastasis as independent prognostic factors for poor OS. However, the addition of anti-angiogenesis therapy to patients with these poor prognostic factors improved OS to levels similar to those without these poor prognostic factors. CONCLUSION: First-line combination EGFR-TKI plus anti-angiogenesis therapy improves PFS in patients with stage IV EGFR-mutant NSCLC. Adding an anti-angiogenesis drug at any line to patients harboring L858R mutation with pleural, liver, or bone metastases can provide survival benefits.

The optimal therapy strategy for epidermal growth factor receptor-mutated non-small cell lung cancer patients with brain metastasis: A real-world study from Taiwan.

BACKGROUND: The treatment options for epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) with brain metastases (BMs) include EGFR-tyrosine kinase inhibitors (TKIs), stereotactic radiosurgery (SRS), whole-brain radiotherapy, brain surgery, and antiangiogenesis therapy. As treatment options evolve, redefining optimal treatment strategies to improve survival are crucial. METHODS: A total of 150 EGFR-mutant NSCLC patients with BMs who received first- or second-generation EGFR-TKIs as first-line treatment between January 2012 and October 2019 were included in this analysis. RESULTS: After multivariate analysis, patients with the graded prognostic assessment for lung cancer using molecular markers (Lung-mol GPA) ≥3 (hazard ratio [HR]: 0.538, 95% confidence interval [CI]: 0.35-0.83), who received afatinib or erlotinib as first-line treatment (HR: 0.521, 95% CI: 0.33-0.82), underwent SRS therapy (HR: 0.531, 95% CI: 0.32-0.87), or were sequentially treated with osimertinib (HR: 0.400, 95% CI: 0.23-0.71) were associated with improved overall survival (OS). Furthermore, SRS plus EGFR-TKI provided more OS benefits in patients with Lung-mol GPA ≥3 compared with EGFR-TKI alone in our patient cohort (44.9 vs. 26.7 months, p = 0.005). The OS in patients who received sequential osimertinib therapy was significantly longer than those without osimertinib treatment (43.5 vs. 24.3 months, p < 0.001), regardless of T790 mutation status (positive vs. negative vs. unknown: 40.4 vs. 54.6 vs.43.4 months, p = 0.227). CONCLUSIONS: The study demonstrated that EGFR-mutant NSCLC patients with BMs could be precisely treated with SRS according to Lung-mol GPA ≥3. Sequential osimertinib was associated with prolonged survival, regardless of T790M status.

The Risk of Herpes Zoster in Women with Polycystic Ovary Syndrome: A Retrospective Population-Based Study.

Background: The association between polycystic ovary syndrome (PCOS) and the risk of herpes zoster (HZ) remains unclear. This study investigated the risk of HZ in women with PCOS. Methods: This study used data from the Longitudinal Generation Tracking Database (LGTD 2005) which contains the information of 2 million randomly selected from National Health Insurance beneficiaries. Patients who received a diagnosis of PCOS between 2000 and 2017 were included in the PCOS cohort. Patients who were not diagnosed as having PCOS were randomly selected from the LGTD 2005 and included in the control cohort. Patients who were aged <20 years and had a history of HZ before the index date were excluded. Patients who were in both the cohorts were matched at a ratio of 1:1 through propensity score matching based on age, comorbidities, and medication. The primary outcome was the diagnosis of HZ. Results: A total of 20,142 patients were included in each case and control cohorts. The incidence rates of HZ in the PCOS and control cohorts were 3.92 and 3.17 per 1000 person-years, respectively. The PCOS cohort had a significantly higher risk of HZ than did the control cohort (adjusted hazard ratios [aHR] = 1.26). Among the patients aged 30−39 years, those with PCOS had a significantly higher risk of HZ than did those without PCOS (aHR = 1.31). Among the patients without any comorbidities, those with PCOS had a significantly higher risk of HZ (aHR = 1.26) than did those without PCOS. Conclusion: PCOS is associated with the risk of HZ, especially in young women. The risk of HZ should be addressed while treating patients with PCOS. An HZ vaccine is recommended for these patients.

The Feasibility of Interventional Pulmonology Methods for Detecting the T790M Mutation after the First or Second-Generation EGFR-TKI Resistance of Non-Small Cell Lung Cancer.

The development of third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) targeting T790M-mutant non-small cell lung cancer (NSCLC) has raised the importance of re-biopsy after EGFR-TKI failure. This study aimed to investigate the feasibility of interventional pulmonology (IP) procedures as re-biopsy methods for identifying the T790M mutation in EGFR-TKI-resistant patients. One hundred and thirty-nine NSCLC patients who underwent IP procedures for re-biopsy as their initial investigation after EGFR-TKI treatment failure were enrolled in this study between January 2020 and August 2022. All patients underwent a first re-biopsy with IP methods, with a diagnostic yield of 81.2% and T790M mutation detection rate of 36%. Thirty patients underwent a second re-biopsy; IP methods were used for 17 (56.6%) patients and non-IP methods for 13 (43.4%) patients; the T790M mutation detection rate was 36.4%. Only six patients underwent a third re-biopsy; no T790M mutation was noted. The T790M mutation detection rate did not differ between IP and non-IP methods (33.6 % vs. 37.5%, p = 0.762). In 11 cases (7.5%), a re-biopsy revealed histologic transformation from lung adenocarcinoma. IP procedures, as first-line re-biopsy methods for NSCLC, are feasible and provide sufficient tissue for identification of the resistance mechanism and target gene T790M mutation.

l-lactic acidosis confers insensitivity to PKC inhibitors by competing for uptake via monocarboxylate transporters.

Targeting protein kinase C (PKC) family was found to repress the migration and resistance of non-small cell lung cancer cells to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). However, none of the PKC inhibitors has been approved for anticancer therapy yet due to the limited efficacy in clinical trials, and the underlying mechanisms remain unclear. l-lactic acidosis, a common condition comprising high l-lactate concentration and acidic pH in the tumor microenvironment, has been known to induce tumor metastasis and drug resistance. In this study, l-lactic acid was found to reverse the inhibitory effects of pan-PKC inhibitors GO6983 on PKC activity, cell migration, and EGFR-TKI resistance, but these effects were not affected by the modulators of lactate receptor GPR81. Interestingly, blockade of lactate transporters, monocarboxylate transporter-1 and -4 (MCT1 and MCT4), attenuated the intracellular level of GO6983, and its inhibitory effect on PKC activity, suggesting that lactic acid promotes the resistance to PKC inhibitors by competing for the uptake through these transporters rather than by activating its receptor, GPR81. Our findings explain the underlying mechanisms of the limited response of PKC inhibitors in clinical trials.