Baseline plasma KL-6 level predicts adverse outcomes in patients with idiopathic pulmonary fibrosis receiving nintedanib: a retrospective real-world cohort study.

BACKGROUND: Nintedanib is effective for treating idiopathic pulmonary fibrosis (IPF), but some patients may exhibit a suboptimal response and develop on-treatment acute exacerbation (AE-IPF), hepatic injury, or mortality. It remains unclear which patients are at risk for these adverse outcomes. METHODS: We analysed the demographic and clinical data, baseline plasma levels of Krebs von den Lungen-6 (KL-6) and surfactant protein A (SPA), and longitudinal clinical courses of a real-world cohort of IPF patients who received nintedanib ≥ 14 days between March 2017 and December 2020. Cox proportional-hazards regression, subdistribution hazards regression, and sensitivity analyses were performed to investigate the association between baseline predictors and AE-IPF, mortality, and nintedanib-related hepatic injury. The relationship between baseline predictors and pulmonary function decline was determined. RESULTS: Fifty-seven patients were included, of whom 24 (42%) developed hepatic injury, 20 (35%) had AE-IPF, and 16 (28%) died on-treatment. A baseline plasma KL-6 level ≥ 2.5 ng/mL, and diffusion capacity for carbon monoxide (DLCO) < 55% predicted, were associated with increased risk of hepatic injury (adjusted hazard ratio [aHR] was 3.46; 95% CI 1.13-10.60; p = 0.029 for KL-6, and 6.05; 95% CI 1.89-19.32; p = 0.002 for DLCO). Both factors also predicted severe and recurrent hepatic injury. Patients with baseline KL-6 ≥ 2.5 ng/mL also had a higher risk of AE-IPF (aHR 4.52; 95% CI 1.63-12.55; p = 0.004). For on-treatment mortality, baseline KL-6 ≥ 3.5 ng/mL and SPA ≥ 600 pg/mL were significant predictors (aHR 5.39; 95% CI 1.16-24.97; p = 0.031 for KL-6, and aHR 12.28; 95% CI 2.06-73.05; p = 0.006 for SPA). Results from subdistribution hazard regression and sensitivity analyses supported these findings. Patients with elevated baseline plasma KL-6 levels also exhibited a trend towards faster pulmonary function decline. CONCLUSIONS: For patients with IPF who are receiving nintedanib, we have identified baseline predictors, in particular plasma KL-6 levels, for the risk of adverse outcomes. Patients with these predictors may require close monitoring for unfavourable responses during treatment. Our findings also support the prognostic role of molecular markers like KL-6 and may contribute to future formulation of more individualized therapeutic strategies for IPF.

Helicobacter pylori test-and-treat program can be cost-effective to prevent gastric cancer in Taiwanese adults: referred to the nationwide reimbursement database.

BACKGROUND: Helicobacter pylori infection increases the risk of gastric cancer. The study aimed to compare cost-effectiveness ratios of H. pylori test-and-treat programs to prevent gastric cancer in Taiwan, referring to the nationwide reimbursement database and expected years of life lost. MATERIALS AND METHODS: During 1998-2009, there were 12,857 females and 24,945 males with gastric adenocarcinoma in Taiwan National Cancer Registry. They were followed up to 2010 and linked to the reimbursement database of National Health Insurance and the national mortality registry to determine lifetime health expenditures and expected years of life lost. Cost-effectiveness ratios of H. pylori test-and-treat programs for prevention of gastric adenocarcinoma were compared between screenings with (13) C-urea breath test and with anti-H. pylori IgG. RESULTS: The test-and-treat program with anti-H. pylori IgG to prevent gastric adenocarcinoma had lower incremental cost-effectiveness ratios than that with (13) C-urea breath test in both sexes (females: 244 vs 1071 US dollars/life-year; males: 312 vs 1431 US dollars/life-year). Cost saving would be achieved in an endemic area where H. pylori prevalence was >73.5%, or by selecting subpopulations with high absolute risk reduction rates of cancer after eradication. Moreover, expected years of life lost of gastric adenocarcinoma were higher and the incremental cost-effectiveness ratios of test-and-treat programs were more cost-effective in young adults (30-69 y/o) than in elders (≥70 y/o). CONCLUSIONS: The test-and-treat program with anti-H. pylori IgG shall be cost-effective to prevent gastric adenocarcinoma in a high endemic area, especially beginning at 30 years of age when H. pylori prevalence rates become stabilized.

Navigating the challenges of invasive pulmonary aspergillosis in lung cancer treatment: a propensity score study.

Background: Invasive pulmonary aspergillosis (IPA) can negatively impact cancer patients' survival. It remains uncertain whether IPA's impact on patient outcomes varies by treatment approach in advanced lung cancer. Objectives: To explore the association between IPA and outcomes in patients with advanced lung cancer receiving different treatments. Design: A retrospective cohort study. Methods: We enrolled patients with advanced-stage lung cancer between 2013 and 2021 at a college hospital in Taiwan and used the 2021 European Organization for Research and Treatment of Cancer/Mycoses Study Group Education and Research Consortium consensus for IPA diagnosis. Multivariable logistic regression was used to identify the IPA risk factors. We compared overall survival (OS) and postgalactomannan (GM) test survival between the IPA and control groups using multivariable Cox proportional hazards regression and the Kaplan-Meier method with propensity score matching (PSM). Results: Among 2543 patients with advanced-stage lung cancer, 290 underwent a GM test, of which 34 (11.7%) were diagnosed with IPA. Patients undergoing chemotherapy (HR = 4.02, p = 0.027) and immunotherapy [hazard ratio (HR) = 3.41, p = 0.076] tended to have IPA. Compared to the control group, the IPA group had shorter median OS (14.4 versus 9.9 months, p = 0.030) and post-GM test survival (4.5 versus 1.9 months, p = 0.003). IPA was associated with shorter OS (log-rank p = 0.014 and 0.018 before and after PSM, respectively) and shorter 1-year and 2-year survival post-GM test (HR = 1.65 and 1.66, respectively). Patients receiving chemotherapy or immunotherapy had a shorter post-GM test survival if they had IPA. Conclusions: IPA tended to be diagnosed more frequently in patients receiving chemotherapy or immune checkpoint inhibitors. Patients diagnosed with IPA are associated with shorter survival. Larger cohort studies are needed to verify the observations.

Chemotherapy outcomes in EGFR-TKI resistant patients with common and uncommon EGFR mutation: An exploratory retrospective cohort study.

BACKGROUND: Some prospective studies have shown that second-generation tyrosine kinase inhibitors (TKIs) provide better control in patients with non-small cell lung cancer (NSCLC) with uncommon epidermal growth factor receptor (EGFR) mutations. However, studies comparing second-line chemotherapy efficacy between NSCLC patients with common and uncommon EGFR mutations remain rare. This retrospective study compared treatment outcomes in these patients. METHODS: Patients with EGFR-mutated advanced-stage NSCLC who received first-line EGFR-TKIs in a tertiary referral center were retrospectively reviewed between January 2010 and August 2022. Patients with a negative T790M test at disease progression who received second-line chemotherapy were enrolled. We compared progression-free (PFS) and overall (OS) survival between advanced NSCLC patients with common and uncommon EGFR mutations using Kaplan-Meier and log-rank tests. RESULTS: In total, 209 (54.8%) patients had a negative T790M mutation test and received second-line chemotherapy, of which 192 (91.8%) had a common EGFR mutation (exon 19 deletion or exon 21 L858R substitution), and 17 (8.2%) had an uncommon EGFR mutation. Patients with common EGFR mutations had significantly longer PFS than those with uncommon EGFR mutations (4.57 vs. 2.57 months, p = 0.031). A Cox proportional hazard regression analysis controlling for potential confounding factors indicated that an uncommon EGFR mutation was an independent prognostic factor for PFS. CONCLUSION: This study suggests that patients with uncommon EGFR mutations have poorer chemotherapy responses and shorter survival than those with common EGFR mutations. The development of new treatment strategies for these patients remains an unmet need.

Low neutrophil-to-lymphocyte ratio predicts overall survival benefit in advanced NSCLC patients with low PD-L1 expression and receiving chemoimmunotherapy.

Although combination therapy including chemotherapy and immune checkpoint inhibitors (ICIs) improves overall survival (OS) of patients with non-small-cell lung cancer (NSCLC), there is a higher incidence of adverse events and treatment discontinuation. Since programmed death-ligand 1 (PD-L1) could not serve as a predictive biomarker, we investigated the neutrophil-to-lymphocyte ratio (NLR) as a predictive biomarker. In our previous research, we demonstrated that a low NLR could predict survival benefits when patients with high PD-L1 expression (> 50%) received chemoimmunotherapy as opposed to immunotherapy alone. In this current study, our objective is to evaluate this predictive capacity in patients with low PD-L1 expression (< 50%). A total of 142 patients were enrolled, 28 receiving combination therapy and 114 receiving chemotherapy alone. Progression-free survival (PFS) and OS were estimated using the Kaplan-Meier method and compared using the log-rank test. Patients who received combination therapy had significantly better PFS and OS than those who received monotherapy. In the subgroup of patients with low NLR, those who received combination therapy exhibited extended PFS and OS with clinical significance, which was also confirmed by multivariate Cox regression analysis. Our study demonstrates the potential use of NLR as a biomarker for predicting survival benefits when receiving combination therapy with chemotherapy and ICIs in patients with advanced NSCLC and low PD-L1 expression.

Cigarette smoke increases susceptibility of alveolar macrophages to SARS-CoV-2 infection through inducing reactive oxygen species-upregulated angiotensin-converting enzyme 2 expression.

Alveolar macrophages (AMs) are the drivers of pulmonary cytokine storm in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. This study aimed to investigate clinical-regulatory factors for the entrance protein of SARS-CoV-2, angiotensin-converting enzyme 2 (ACE2) in AMs. Human AMs were collected from 56 patients using bronchoalveolar lavage. ACE2 expression in AMs was positively correlated with smoking pack-year (Spearman's r = 0.347, P = 0.038). In multivariate analysis, current smoking was associated with increased ACE2 in AMs (ß-coefficient: 0.791, 95% CI 0.019-1.562, P = 0.045). In vitro study, ex-vivo human AMs with higher ACE2 were more susceptible to SARS-CoV-2 pseudovirus (CoV-2 PsV). Treating human AMs using cigarette smoking extract (CSE) increases the ACE2 and susceptibility to CoV-2 PsV. CSE did not significantly increase the ACE2 in AMs of reactive oxygen species (ROS) deficient Cybb-/- mice; however, exogenous ROS increased the ACE2 in Cybb-/- AMs. N-acetylcysteine (NAC) decreases ACE2 by suppressing intracellular ROS in human AMs. In conclusion, cigarette smoking increases the susceptibility to SARS-CoV-2 by increasing ROS-induced ACE2 expression of AMs. Further investigation into the preventive effect of NAC on the pulmonary complications of COVID-19 is required.

Effect of BIM expression on the prognostic value of PD-L1 in advanced non-small cell lung cancer patients treated with EGFR-TKIs.

The role of Programmed Cell Death Ligand 1 (PD-L1) expression in predicting epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKIs) efficacy remains controversial. Recent studies have highlighted that tumor-intrinsic PD-L1 signaling can be modulated by STAT3, AKT, MET oncogenic pathway, epithelial-mesenchymal transition, or BIM expression. This study aimed to investigate whether these underlying mechanisms affect the prognostic role of PD-L1. We retrospectively enrolled patients with EGFR mutant advanced stage NSCLC who received first-line EGFR-TKI between January 2017 and June 2019, the treatment efficacy of EGFR-TKI was assessed. Kaplan-Meier analysis of progression-free survival (PFS) revealed that patients with high BIM expression had shorter PFS, regardless of PD-L1 expression. This result was also supported by the COX proportional hazard regression analysis. In vitro, we further proved that the knockdown of BIM, instead of PDL1, induced more cell apoptosis following gefitinib treatment. Our data suggest that among the pathways affecting tumor-intrinsic PD-L1 signaling, BIM is potentially the underlying mechanism that affects the role of PD-L1 expression in predicting response to EGFR TKI and mediates cell apoptosis under treatment with gefitinib in EGFR-mutant NSCLC. Further prospective studies are required to validate these results.

Development and validation of a prediction index for recent mortality in advanced COPD patients.

The primary barrier to initiating palliative care for advanced COPD patients is the unpredictable course of the disease. We enroll 752 COPD patients into the study and validate the prediction tools for 1-year mortality using the current guidelines for palliative care. We also develop a composite prediction index for 1-year mortality and validate it in another cohort of 342 patients. Using the current prognostic models for recent mortality in palliative care, the best area under the curve (AUC) for predicting mortality is 0.68. Using the Modified Medical Research Council dyspnea score and oxygen saturation to define the combined dyspnea and oxygenation (DO) index, we find that the AUC of the DO index is 0.84 for predicting mortality in the validated cohort. Predictions of 1-year mortality based on the current palliative care guideline for COPD patients are poor. The DO index exhibits better predictive ability than other models in the study.

Improved survival in patients with unresectable stage III EGFR-mutant adenocarcinoma with upfront EGFR-tyrosine kinase inhibitors.

BACKGROUND: Although epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have been the standard treatment for advanced EGFR-mutant adenocarcinoma, the effects of upfront EGFR-TKI use in unresectable stage III EGFR-mutant adenocarcinoma remain unexplored. Here, we conducted a retrospective study to compare different treatment strategies in these patients. METHODS: From October 2010 to June 2019, patients with unresectable stage III adenocarcinoma who received treatment at a tertiary referral center were enrolled. Patients were classified into three groups: EGFR-mutant adenocarcinoma treated with concurrent chemoradiotherapy (group 1) or EGFR-TKI (group 2) and EGFR wild-type adenocarcinoma treated with concurrent chemoradiotherapy (group 3). Progression-free survival, progression-free survival-2, and overall survival were estimated and compared using Kaplan-Meier and log-rank tests. RESULTS: A total of 92 patients were enrolled; 10, 40, and 42 patients were assigned to groups 1, 2, and 3, respectively. Patients with EGFR mutations who received upfront EGFR-TKIs had significantly longer progression-free and overall survival than those who received upfront concurrent chemoradiotherapy (hazard ratio 0.33 vs. 0.34, p = 0.006 vs. 0.031) according to a Cox model adjusted for possible confounders. Moreover, upfront concurrent chemoradiotherapy did not lead to higher survival rates in patients with EGFR mutations than in those with EGFR wild-type adenocarcinoma (progression-free survival; hazard ratio 0.37, p = 0.036; overall survival; hazard ratio 0.35, p = 0.080) by Cox regression analysis. CONCLUSION: This current study suggests that EGFR-TKIs is a better choice for patients with unresectable stage III EGFR-mutant adenocarcinoma. However, further randomized studies are required to validate the results.

Pembrolizumab and Chemotherapy Combination Prolonged Progression-Free Survival in Patients with NSCLC with High PD-L1 Expression and Low Neutrophil-to-Lymphocyte Ratio.

The use of immune checkpoint inhibitors (ICIs) has provided overall survival (OS) benefits in patients with treatment-naïve advanced non-small cell lung cancer (NSCLC) without targetable driver mutations. However, studies comparing ICIs monotherapy with combination therapy either with chemotherapy or radiotherapy in programmed death-ligand 1 high expressors remain limited. This study aimed to retrospectively compare the treatment efficacy of the therapies by studying 47 patients with treatment-naïve advanced NSCLC who received ICI monotherapy (n = 28) or combination therapy either with chemotherapy or radiotherapy (n = 19). Progression-free survival (PFS) and OS were estimated using the Kaplan-Meier method and compared using log-rank tests. It was observed that patients who received combination therapy had a better PFS than monotherapy, but no such significant benefit was observed in OS. The difference in PFS was higher in the subgroup of patients with low neutrophil-to-lymphocyte ratio (NLR) than in the high-NLR patient subgroup. This study suggests that pembrolizumab in combination with chemotherapy or radiotherapy could provide a significant benefit in PFS, especially in patients with treatment-naïve advanced NSCLC with low NLR. Furthermore, our study also demonstrates the potential use of NLR as a biomarker for prediction of treatment outcomes in patients with advanced NSCLC receiving combination therapy.

The impact of driver mutation on the treatment outcome of early-stage lung cancer patients receiving neoadjuvant immunotherapy and chemotherapy.

Neoadjuvant immunotherapy and chemotherapy have improved the major pathological response (MPR) in patients with early-stage operable non-small cell lung cancer (NSCLC). This study aimed to assess whether the presence of targetable driver mutations affects the efficacy of the combination of immunotherapy and chemotherapy. We enrolled patients with early-stage operable NSCLC who received preoperative neoadjuvant therapy between January 1, 2017, and December 30, 2020. Neoadjuvant therapy was delivered with platinum-doublet chemotherapy; moreover, pembrolizumab was added at the attending physician's discretion based on patient's request. Pathological responses were assessed; moreover, disease-free survival was estimated. Next-generation sequencing was performed in case sufficient preoperative biopsy specimens were obtained. We included 23 patients; among them, 11 received a combination of neoadjuvant immunotherapy and chemotherapy while 12 received neoadjuvant chemotherapy alone. The MPR and pathological complete response rates were 54.5% and 27.3%, respectively, in patients who received a combination of neoadjuvant immunotherapy and chemotherapy. These rates were significantly higher than those in patients who only received neoadjuvant chemotherapy. Three patients in the combination group experienced disease recurrence during the follow-up period even though two of them showed an MPR. These three patients had targetable driver mutations, including an EGFR exon 20 insertion, EGFR exon 21 L858R substitution, and MET exon 14 skipping. Only one patient who remained disease-free had a targetable driver mutation. Among patients with early-stage operable NSCLC requiring neoadjuvant therapy, comprehensive genomic profiling is crucial before the administration of the combination of neoadjuvant immunotherapy and chemotherapy.

First-line treatment with irreversible tyrosine kinase inhibitors associated with longer OS in EGFR mutation-positive non-small cell lung cancer.

BACKGROUND: Few studies have compared the efficacy of the irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), afatinib, with that of reversible EGFR-TKIs. Therefore, this study assessed the effectiveness of afatinib, erlotinib, and gefitinib in terms of OS (overall survival) and progression-free survival (PFS) in EGFR mutation-positive advanced non-small cell lung cancer (NSCLC) patients. METHODS: Patients with EGFR mutation-positive advanced NSCLC who sought treatment from December 2013 to June 2018, at a tertiary referral center were retrospectively analyzed. These patients were treated with afatinib or a reversible EGFR-TKI (erlotinib or gefitinib) until disease progression, intolerable adverse events, or death. The Kaplan-Meier and log-rank tests were then used to compare the OS and PFS of the patients. We further analyzed the survival differences among the subgroup of patients without brain metastases. RESULTS: Of the 363 patients enrolled, 134 and 229 received first-line afatinib and first-line reversible EGFR-TKI, respectively. Those given afatinib had better OS (39.3 vs. 26.0 months; HR 0.65, P = 0.033) and PFS (14.1 vs.11.2 months; HR 0.58, P < 0.001). Of the 246 patients without brain metastases, 93 and 153 received first-line afatinib and a first-line reversible EGFR-TKI, respectively. Those given afatinib had a better OS (52.6 vs. 24.9 months; HR 0.62, P = 0.0030) and PFS (17.7 vs. 11.1 months; HR 0.51, P < 0.001). The survival benefit was more significant in the subgroup of patients with L858R substitutions. CONCLUSIONS: The results indicated that afatnib resulted in significantly better OS and PFS than gefitnib and erlotinib for EGFR mutation-positive advanced NSCLC patients without brain metastases. KEY POINTS: Significant findings of the study Afatnib resulted in significantly better overall survival and progression-free survival than gefitnib and erlotinib for EGFR mutation-positive advanced non-small cell lung cancer patients without brain metastases. What this study adds This study helps fill the gap in our limited understanding of the differences in the efficacy of the irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), afatinib, with that of reversible EGFR-TKIs.