Correlating Reiff scores with clinical, functional, and prognostic factors: characterizing noncystic fibrosis bronchiectasis severity: validation from a nationwide multicenter study in Taiwan.

BACKGROUND: Our study aimed to confirm a simplified radiological scoring system, derived from a modified Reiff score, to evaluate its relationship with clinical symptoms and predictive outcomes in Taiwanese patients with noncystic fibrosis bronchiectasis (NCFB). METHODS: This extensive multicenter retrospective study, performed in Taiwan, concentrated on patients diagnosed with NCFB verified through high-resolution computed tomography (HRCT) scans. We not only compared the clinical features of various types of bronchiectasis (cylindrical, varicose, and cystic). Furthermore, we established relationships between the severity of clinical factors, including symptom scores, pulmonary function, pseudomonas aeruginosa colonization, exacerbation and admission rates, and HRCT parameters using modified Reiff scores. RESULTS: Data from 2,753 patients were classified based on HRCT patterns (cylindrical, varicose, and cystic) and severity, assessed by modified Reiff scores (mild, moderate, and severe). With increasing HRCT severity, a significant correlation was found with decreased forced expiratory volume in the first second (FEV1) (p < 0.001), heightened clinical symptoms (p < 0.001), elevated pathogen colonization (pseudomonas aeruginosa) (p < 0.001), and an increased annual hospitalization rate (p < 0.001). In the following multivariate analysis, elderly age, pseudomonas aeruginosa pneumonia, and hospitalizations per year emerged as the only independent predictors of mortality. CONCLUSION: Based on our large cohort study, the simplified CT scoring system (Reiff score) can serve as a useful adjunct to clinical factors in predicting disease severity and prognosis among Taiwanese patients with NCFB.

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.

Application of impulse oscillometry to detect interstitial lung disease and airway disease in adults with rheumatoid arthritis.

BACKGROUND: We conducted a retrospective observational study to explore the potential application of impulse oscillometry (IOS) as an alternative to high-resolution computed tomography (HRCT) for detecting pulmonary involvement in patients with rheumatoid arthritis (RA) because clinically evident interstitial lung disease (ILD) and airway involvement are common in this population. METHODS: We enrolled 72 patients with RA who underwent pulmonary function tests (PFTs) and IOS between September 2021 and September 2022. We aimed to identify the PFT and IOS variables associated with lung diseases shown on HRCT images. RESULTS: In our cohort of 72 patients, 48 underwent HRCT; of these, 35 had airway disease or ILD and 13 showed no obvious abnormalities on HRCT. Abnormal IOS and PFT parameters were observed in 34 and 23 patients, respectively, with abnormal HRCT images. The predicted percentages for forced vital capacity, the ratio of forced expiratory volume in the first one second to forced vital capacity, and forced mid-expiratory flow value were significantly lower in patients with abnormal HRCT. Lung resistance at 5 Hz, difference in resistance between 5 and 20 Hz, resonant frequency (Fres), and reactance area were higher in these patients and reactance at 5 Hz was lower. Compared to other parameters, Fres > 14.14 was significantly associated with alterations in HRCT and may be used as an indicator for monitoring disease. CONCLUSION: Fres > 14.14 is significantly associated with lung involvement in RA patients. Performance of spirometry with IOS is more beneficial than spirometry alone for evaluating lung involvement in RA patients.

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.

The clinical efficacy of cefoperazone-sulbactam versus piperacillin-tazobactam in the treatment of severe community-acquired pneumonia.

The objective was to compare the clinical efficacy of cefoperazone-sulbactam with piperacillin-tazobactam in the treatment of severe community-acquired pneumonia (SCAP). The retrospective study was conducted from March 1, 2018 to May 30, 2019. Clinical outcomes were compared for patients who received either cefoperazone-sulbactam or piperacillin-tazobactam in the treatment of SCAP. A total of 815 SCAP patients were enrolled. Among them, 343 received cefoperazone-sulbactam, and 472 received piperacillin-tazobactam. Patients who received cefoperazone-sulbactam presented with higher Charlson Comorbidity Index scores. (6.20 ± 2.77 vs 5.72 ± 2.61; P = .009). The clinical cure rates and effectiveness for patients receiving cefoperazone-sulbactam and piperacillin-tazobactam were 84.2% versus 80.3% (P = .367) and 85.4% versus 83.3% (P = .258), respectively. In addition, the overall mortality rate of the cefoperazone-sulbactam group was 16% (n = 55), which was also comparable to the piperacillin-tazobactam group (17.8%, n = 84, P = .572). The primary clinical outcomes for patients receiving cefoperazone-sulbactam were superior compared to those receiving piperacillin-tazobactam after adjusting disease severity status. The clinical efficacy of cefoperazone-sulbactam in the treatment of adult patients with SCAP is comparable to that of piperacillin-tazobactam. After adjusting for disease severity, cefoperazone-sulbactam tended to be superior to piperacillin-tazobactam.

Outcomes and Prognostic Factors in Critical Patients with Hematologic Malignancies.

Patients with hematologic malignancies (HMs) have a significantly elevated risk of mortality compared to other cancer patients treated in the intensive care unit (ICU). The prognostic impact of numerous poor outcome indicators has changed, and research has yielded conflicting results. This study aims to determine the ICU and hospital outcomes and risk factors that predict the prognosis of critically ill patients with HMs. In this retrospective study, conducted at a referral hospital in Taiwan, 213 adult patients with HMs who were admitted to the medical ICU were evaluated. We collected clinical data upon hospital and ICU admission. Using a multivariate regression analysis, the predictors of ICU and hospital mortality were assessed. Then, a scoring system (Hospital outcome of critically ill patients with Hematological Malignancies (HHM)) was built to predict hospital outcomes. Most HMs (76.1%) were classified as high grade, and more than one-third of patients experienced a relapsed or refractory disease. The ICU and hospital mortality rates were 55.9% and 71.8%, respectively. Moreover, the disease severity was high (median Sequential Organ Failure Assessment (SOFA) score: 11 and Acute Physiology and Chronic Health Evaluation (APACHE II) score: 28). The multivariate analysis revealed that high-grade HMs, invasive mechanical ventilation requirement, renal replacement therapy initiation in the ICU, and a high SOFA score correlated with ICU mortality. Furthermore, a higher HHM score predicted hospital mortality. This study demonstrates that ICU mortality primarily correlates with the severity of organ dysfunction, whereas the disease status markedly influences hospital outcomes. Furthermore, the HHM score significantly predicts hospital mortality.

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.

Differences in Pulmonary Function Improvement after Once-Daily LABA/LAMA Fixed-Dose Combinations in Patients with COPD.

This real-world study evaluated the efficacy of once-daily long-acting ß2-agonist (LABA)/long-acting muscarinic antagonist (LAMA) fixed-dose combinations (FDCs) for improving lung function in patients with chronic obstructive pulmonary disease (COPD). Patients with COPD who were treated with once-daily LABA/LAMA FDCs for 12 months were included. We evaluated their lung function improvement after 12 months of treatment with different LABA/LAMA FDCs. A total of 198 patients with COPD who were treated with once-daily LABA/LAMA FDCs were analyzed. A total of 114 patients were treated with umeclidinium/vilanterol (UMEC/VIL); 34 patients were treated with indacaterol/glycopyrronium (IND/GLY); and 50 patients were treated with tiotropium/olodaterol (TIO/OLO). The forced expiratory volume in 1 s (FEV1) was significantly increased in the patients treated with all three once-daily FDCs (55.2% to 60.9%, p = 0.012 for UMEC/VIL, 58.2% to 63.6%, p = 0.023 for IND/GLY, and 54.1% to 57.7%, p = 0.009 for TIO/OLO). The treatment of COPD patients with TIO/OLO resulted in a significant improvement in both forced vital capacity (FVC%) (71.7% to 77.9%, p = 0.009) and residual volume (RV%) (180.1% to 152.5%, p < 0.01) compared with those treated with UMEC/VIL (FVC%: 75.1% to 81.5%, p < 0.001; RV%:173.8% to 165.2%, p = 0.231) or IND/GLY (FVC%: 73.9% to 79.3%, p = 0.08; RV%:176.8% to 168.3%, p = 0.589). Patients treated with UMEC/VIL or TIO/OLO showed significant improvement in FVC. In addition, those receiving TIO/OLO also showed significant improvement in RV reduction.

Ischemic stroke in a patient with EGFR-mutated non-small-cell lung cancer after treatment with ramucirumab.

Vascular endothelial growth factor (VEGF) inhibitors have been widely investigated in the last 10 years, with particular attention paid to their adverse effects because of their efficacy in improving cancer patient survival. Previous research primarily focused on the monoclonal anti-vascular endothelial growth factor antibody bevacizumab and its adverse outcomes. Reports show a higher risk of ischemic stroke, one of the most concerning clinically relevant events, after treatment with bevacizumab. However, few studies have examined the relationship between anti-VEGF receptor 2 monoclonal antibody ramucirumab and its adverse events. This article presents the case of a non-small-cell lung cancer patient who experienced a new ischemic stroke after treatment with ramucirumab. The findings suggest that further studies may be necessary to investigate the relationship between ramucirumab and the risk of ischemic stroke.

Concurrent aspergillosis and cystic pulmonary metastases in a patient with tongue squamous cell carcinoma.

Pulmonary Aspergillus infection may have a variety of manifestations depending on the patients' immunity status and pre-existing lung conditions. Radiographically, aspergilloma, which is usually associated with noninvasive Aspergillus fumigatus conidia, may feature a characteristic mass in a cavity commonly located in the upper lobes of the lung. It is typically encountered upon pre-existing lung damage. Here we report Aspergillus growing in a pulmonary metastatic cavity in a 47-year-old male worker with a history of tongue cancer after a radical operation with neck dissection and concurrent chemotherapy in 2014. Chest radiography and computed tomography showed a cavitary lesion with a ball-in-hole lesion in the right upper lobe (RUL) and two cystic lesions within the bilateral upper lung field. Endobronchial ultrasound-guided transbronchial biopsy (EBUS-TBB) from the RUL anterior segmental bronchus (RB3) revealed the presence of Aspergillus conidia and squamous cell carcinoma. Wedge resection of the cystic lesion within the left upper lobe confirmed the diagnosis of metastatic squamous cell carcinoma. This is a rare case of aspergillosis within cavities of pulmonary metastases in a patient who was diagnosed with tongue squamous cell carcinoma. The conclusive distinction between neoplasm and fungal infection is difficult to achieve by radiography, and a pathological biopsy by EBUS-TBB is necessary to aid diagnosis. Clinicians should be aware of such an atypical presentation of metastases coexisting with Aspergillus infection.

A rare presentation of anaplastic large cell lymphoma as a cavitary pulmonary mass with hypercalcemia.

Cavitary lung lesions found on chest imaging may point to various diseases. These lesions may be caused by numerous etiologies, such as infection, inflammatory diseases, or malignancy. Thus, its etiology may be challenging to differentiate using imaging alone. Differential diagnoses are created using a combination of clinical symptoms, medical history, laboratory results, and physical examination. Primary pulmonary lymphoma and anaplastic large cell lymphoma (ALCL) are rare differentials. Here, we report a case of ALCL that initially presented with back pain, intermittent fever, hemoptysis, hypercalcemia, and bilateral multiple cavitary lung nodules. Because a cavitary pulmonary mass with sustained hypercalcemia is commonly seen in patients with squamous cell carcinomas or pulmonary tuberculosis, patients with ALCL may be misdiagnosed and undergo delayed treatment. This study highlights that ALCL should be considered in patients presenting with a cavitary pulmonary mass and hypercalcemia.

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.

Pendulone induces apoptosis via the ROS-mediated ER-stress pathway in human non-small cell lung cancer cells.

PURPOSE: Pendulone, an isoflavone compound, is known to act against human cancer cells. However, its role in human non-small cell lung cancer (NSCLC) and the exact molecular mechanisms of action have never been reported. METHODS: We investigated the effects of pendulone on cell proliferation and apoptosis in human NSCLC H1299 cells. Cell viability was examined using the methyl-thiazol-diphenyl-tetrazolium (MTT) assay. Flow cytometry was employed to evaluate apoptotic indices such as the cell cycle, mitochondrial membrane potential, cytochrome c release, caspase activity, and death receptor expression. The expression of proteins related to the cell cycle and apoptosis were analyzed by Western blot analysis. RESULTS: Pendulone significantly decreased H1299 cell viability by inducing endoplasmic reticulum (ER) stress through the accumulation of reactive oxygen species (ROS). Pendulone induced the expression of ER stress-associated proteins, such as ATF4 and CHOP, which promoted the expression of death receptors. Activation of caspase 8 induced extrinsic pathway apoptosis. Pendulone also caused the loss of mitochondrial membrane potential, inhibited the anti-apoptotic proteins BCL-2 and activated the pro-apoptotic protein BAX, which promoted the release of cytochrome c to activate caspase 9. Antioxidant N-acetylcysteine (NAC), with its ROS-suppressive property, reversed pendulone-induced ER stress and cell apoptosis. CONCLUSION: Our findings provide evidence that pendulone induces apoptosis by inducing ER stress through ROS accumulation and mitochondrial dysfunction in NSCLC cell lines.

Bevacizumab plus dacomitinib combination therapy for L858R-mutated metastatic lung adenocarcinoma: A report of two cases.

Dual inhibition of the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor pathways for the treatment for EGFR-mutated, metastatic non-small cell lung cancer is supported by previous randomized controlled trials. However, the use of second-generation irreversible EGFR tyrosine kinase inhibitor (TKI) dacomitinib in combination with antiangiogenic therapy has not been reported in the literature. Here, we report the case of a 73-year-old man who presented with hemoptysis and dyspnea on exertion and was diagnosed with right upper lung adenocarcinoma with pleural metastasis and L858R mutation. The second case is of a 60-year-old woman who presented with low back pain and was diagnosed with right lower lung adenocarcinoma with bone metastasis and L858R mutation. Both patients underwent first-line therapy with the TKI dacomitinib in combination with bevacizumab. The first patient showed a nearly complete response, and the second patient showed a partial response after the combination therapy and no severe side effects.

(-)-Agelasidine A Induces Endoplasmic Reticulum Stress-Dependent Apoptosis in Human Hepatocellular Carcinoma.

Liver cancers, such as hepatocellular carcinoma (HCC), are a highly prevalent cause of cancer-related deaths. Current treatments to combat liver cancer are limited. (-)-Agelasidine A, a compound isolated from the methanol extract of Agelasnakamurai, a sesquiterpene guanidine derived from sea sponge, has antibacterial activity. We demonstrated its anticancer capabilities by researching the associated mechanism of (-)-agelasidine A in human liver cancer cells. We found that (-)-agelasidine A significantly reduced viability in Hep3B and HepG2 cells, and we determined that apoptosis was involved in the (-)-agelasidine A-induced Hep3B cell deaths. (-)-Agelasidine A activated caspases 9, 8, and 3, as well as PARP. This effect was reversed by caspase inhibitors, suggesting caspase-mediated apoptosis in the (-)-agelasidine A-treated Hep3B cells. Moreover, the reduced mitochondrial membrane potential (MMP) and the release of cytochrome c indicated that the (-)-agelasidine A-mediated mitochondrial apoptosis was mechanistic. (-)-Agelasidine A also increased apoptosis-associated proteins (DR4, DR5, FAS), which are related to extrinsic pathways. These events were accompanied by an increase in Bim and Bax, proteins that promote apoptosis, and a decrease in the antiapoptotic protein, Bcl-2. Furthermore, our results presented that (-)-agelasidine A treatment bridged the intrinsic and extrinsic apoptotic pathways. Western blot analysis of Hep3B cells treated with (-)-agelasidine A showed that endoplasmic reticulum (ER) stress-related proteins (GRP78, phosphorylated PERK, phosphorylated eIF2α, ATF4, truncated ATF6, and CHOP) were upregulated. Moreover, 4-PBA, an ER stress inhibitor, could also abrogate (-)-agelasidine A-induced cell viability reduction, annexin V+ apoptosis, death receptor (DR4, DR5, FAS) expression, mitochondrial dysfunction, and cytochrome c release. In conclusion, by activating ER stress, (-)-agelasidine A induced the extrinsic and intrinsic apoptotic pathways of human HCC.

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.

A Real World Study to Assess the Effectiveness of Switching to Once Daily Closed Triple Therapy from Mono/Dual Combination or Open Triple Therapy in Patients with Chronic Obstructive Pulmonary Disease.

Objective: This real world study evaluated the effectiveness of switching to closed triple therapy from mono/dual combination or open triple therapy in patients with chronic obstructive pulmonary disease (COPD). Methods: We conducted this retrospective study at a single medical center from December 2014 to September 2020. Patients with COPD who were stepped up to triple therapy were enrolled. We analyzed the duration from initial COPD management to open or closed triple therapy and identified the clinical predictors of the patients who needed triple therapy early. We also evaluated the effectiveness of triple therapy after switching from initial management, and closed triple therapy after switching from open triple therapy. Results: A total 115 COPD patients who were stepped up to triple therapy from initial treatment were analyzed. The duration from initial treatment to triple therapy was 22.4 months. The baseline peripheral blood eosinophil counts of the patients who switched to triple therapy early (n=63, less than 22 months) and those who switched to triple therapy later (n=52, more than 22 months) were similar (489.6 vs 434.5 cells/uL; p=0.589). After univariate and multivariate analysis, the patients who were older had more acute exacerbations (AEs) in the previous year, asthma and COPD overlap (ACO), and initial dual bronchodilator therapy were stepped up to triple therapy early. The FEV1 of the patients was significantly increased after switching to open triple therapy from mono bronchodilator therapy. In addition, switching from initial or open triple therapy to closed triple therapy significantly reduced the incidence of AEs. Conclusion: COPD patients with high blood eosinophilia, older age, more AEs in the previous year, ACO, and initial dual bronchodilator therapy were stepped up to triple therapy early. Triple therapy showed improvements in lung function of most patients switching from mono bronchodilator therapy. After switching to closed triple therapy further reduced the incidence of AEs.

Acute myeloid leukemia with leukemic pleural effusion and high levels of pleural adenosine deaminase: A case report and review of literature.

Pleural effusions are rarely observed in association with acute myeloid leukemia (AML), and their true incidence remains unknown. Given the low diagnostic yield from cytopathologic analysis of malignant pleural effusions and the fact that patients with leukemia are often thrombocytopenic and unable to tolerate invasive procedures, the incidence of leukemic effusions may be underestimated. Here, we report a rare case of pleural effusion in a patient with newly diagnosed AML. Initial analysis revealed an exudative, lymphocyte-predominant effusion. High levels of adenosine deaminase (ADA) were detected in pleural fluid, consistent with a diagnosis of tuberculosis. However, the analysis of pleural cytology revealed leukemic cells, permitting the diagnosis of leukemic effusion to be made. The patient underwent induction chemotherapy and pleural effusion resolved without recurrence. This case emphasizes the diagnostic dilemma presented by high levels of ADA in a leukemic pleural effusion, as this association has not been previously considered in the literature.