bluuebunny/crossref_metadata_2025_split huggingface dataset:
Anti-neoplastic drugs for malignant pleural effusion in non-small cell lung cancer: A meta-analysis.
Authors: Ababneh Obada Ehab , Syaj Sebawe , Ahmed Yaman Belal , Hatamleh Zaid , Saleh Sara , Zaitoun Alaa , Akhdar Marah , Alsaid Ahmad Mohammad , Al-shdaifat Raghad , Hamouri Shadi 
Published: June 2022

e21060 Background: Malignant pleural effusion (MPE) occurs in 7-23% of advanced non-small cell lung cancer (NSCLC) patients with overall survival (OS) of 8.5 months only. The optimum anti-neoplastic regimen in MPE is yet to be determined. Thus, we conducted a meta-analysis to determine the optimum anti-neoplastic agent in managing MPE in NSCLC. Methods: We searched PubMed, Scopus, CENTRAL, ASCO, ESMO, and IASLC meetings libraries to retrieve relevant trials. We included single-arm and controlled trials in which patients with MPE were treated by anti-neoplastic drugs such as chemotherapy and/or targeted therapy. Patients treated with radiotherapy were excluded. Primary and secondary endpoints were efficacy and safety, respectively. Meta-analysis was conducted for the primary endpoint estimated by OS and objective response rate (ORR). In addition, subgroup analysis was conducted to investigate the effect of route of administration (ROA) and randomization on ORR. Results: We included 11 trials with a total of 542 patients. There were 5 randomized clinical trials, 5 phase II trials, and 1 phase I trial with a total of 16 relevant arms. Five arms used single-agent chemotherapy (SC), 11 combined therapy (CT) and 6 arms bevacizumab-based (BEVA) therapy. The ROA was intrapleural (IP) in 10 arms and intravenous (IV) in 6 arms. We pooled 124 patients from 5 trials that reported ORR results for SC patients. The pooled ORR was 41.7% (95% CI: 32.8 to 50.8%) with no heterogeneity ( I2 = 0%, p = 0.47). Pooling of 396 patients who underwent CT in 10 studies results in an ORR of 64.1% (95% CI: 52.7 to 74.8%) with a high heterogeneity rate ( I2 = 84%, p< 0.01). Analysis of BEVA studies yielded an ORR of 62.2% (95% CI: 43.5 to 79.2%), representing 133 patients from 5 trials. The table shows the effect of randomization and ROA on ORR. One-year OS was reported in 4 studies that used CT; pooled 1-year OS estimate for 216 patients was 81.2% (95% CI: 75.5 to 86.4%). As for grade 3/4 AEs, the occurrence of nausea/vomiting (N/V) was higher in CT than SC (14% vs 2%). Chest pain rate was similar (9.8% vs 7.0%), leukopenia was higher in BEVA than SC (19.1% vs 9.8%), and neutropenia was more prevalent in BEVA than CT (22.1% vs 8.1%). Incidence of any-grade N/V was more common in BEVA than SC (42.9% vs 19.3%). Conclusions: Both CT and BEVA-based regimens were effective and safe in treating MPE. IP was superior to IV in CC and BEVA based regimens. ORR was higher in randomized trials, suggesting a better response of MPE under optimum clinical conditions. Further trials of these agents are needed to confirm these results.[Table: see text]
Overall survival benefits of first-line treatments for Asian patients with advanced epidermal growth factor receptor-mutated non-small cell lung cancer harboring L858R mutation: A systematic review and network meta-analysis.
Authors: Chan Sik-Kwan , Choi Cheuk-Wai , Lee Victor Ho-Fun 
Published: June 2022

e21064 Background: First-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) and their biologically synergistic combinations with other treatments for patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC) as first-line treatment for EGFR-mutant NSCLC have recently gained considerable attention, in particular for those with L858R mutation, a known worse subgroup compared to exon 19 deletions. However, their efficacy, in particular, the long-term overall survival (OS) benefit in Asian patients with the L858R mutation remains unclear. Methods: We performed a systematic review and fixed-effects frequentist network meta-analysis by retrieving relevant literature from PubMed/MEDLINE Ovid, Embase, Cochrane Library, CINAHL Databases, trial registries and other sources. P-score was used to rank the treatments. We included published and gray sources of randomized clinical trials comparing two or more treatments in the first line setting for Asian patients with advanced EGFR mutated NSCLC harboring L858R mutation. This study was registered in the Prospective Register of Systematic Reviews (CRD42022295897). Results: Eighteen trials involved 1852 Asian patients and 12 treatments: including EGFR tyrosine kinase inhibitors (TKIs; osimertinib, dacomitinib, afatinib, erlotinib, gefitinib, and icotinib), pemetrexed-based chemotherapy, pemetrexed-free chemotherapy, and combination treatments (gefitinib plus apatinib, erlotinib plus ramucizumab, erlotinib plus bevacizumab and gefitinib plus pemetrexed-based chemotherapy). Asian patients with the L858R mutation had no significant OS benefits from all EGFR TKIs or combination treatments over chemotherapies. Gefitinib plus pemetrexed-based chemotherapy, dacomitinib, osimertinib and erlotinib plus bevacizumab were shown to be consistent in yielding the best progression-free survival benefit, with their corresponding P-scores of 93%, 79%, 77% and 70%. Combination treatments caused more toxicity in general, especially erlotinib plus bevacizumab and gefitinib plus pemetrexed-based chemotherapy, which caused the most adverse events of grade 3 or higher. Conclusions: In Asian patients with advanced NSCLC harboring L858R mutation, EGFR TKIs and combination treatments demonstrated no OS benefit when compared with conventional chemotherapies. Further studies are warranted to investigate the resistance mechanism with TKIs and potential combination strategies in patients with the L858R mutation.
ANK2 mutation as an indicator stratified patients benefit from immune checkpoint inhibitors in NSCLC.
Authors: Liu Hongbing , Zhao Lele , Liu Yaqin , Xiao Mingzhe , Zhang Qin , Qi Chuang 
Published: June 2022

e21080 Background: Immune checkpoint inhibitors (ICIs), targeting the programmed cell death 1 (PD-1), programmed cell death ligand 1 (PD-L1) or cytotoxic T lymphocyte-associated protein 4 (CTLA-4) have demonstrated impressive anti-tumor efficacy in multiple cancers, in particular with non-small cell lung cancer (NSCLC). However, only a minority of patients could benefit from ICIs. Therefore, investigating predictive biomarkers of ICIs is important to identify the target population that derives the best therapeutic benefit. ANK2 encodes ankyrin-2, which plays a crucial role in cell development. Studies have shown a significant correlation between ANK2 expression levels and clinical outcomes in gastrointestinal cancers and pancreatic cancer. However, its role in lung cancer immunotherapy remains unknown. Here we aimed to demonstrate the association between ANK2 and ICIs. Methods: 165 patients from three public immunotherapy cohorts (Hellmann 2018, Miao 2018, and Rizvi 2015 cohort) were included to analyze the association between ANK2 gene mutation and efficacy of ICI therapy. Genomic, survival and mRNA data of NSCLC patients from the Cancer Genome Atlas (TCGA) database was used to explore the potential mechanisms of anti-tumor immunity. Results: Patients with ANK2 mutation were significantly associated with better PFS (HR = 0.28; 95% CI, 0.15-0.53; P < 0.001), objective response rate (ORR, 69.0% vs 24.3%; P < 0.001) and durable clinical benefit (DCB, 72.4% vs 41.9%; P = 0.003) compared with those with wide-type in NSCLC. ANK2 mutation were associated with increased TMB (P < 0.001). In the multivariable Cox proportional hazards regression model adjusted by the smoking status, PD-L1 expression and TMB, the association between ANK2 mutation and PFS remained significant (HR = 0.28; 95% CI, 0.20-0.82; P = 0.012).In TCGA, no association between ANK2 mutation and OS (LUAD: P =0.27 ; LUSC: P = 0.39) or PFS (LUAD: P = 0.21; LUSC: P = 0.63) was observed, suggesting that ANK2 mutation may be a predictive but not a prognostic factor in ICI treatment for NSCLC patients. Based on CIBERSORT-inferred tumor infiltrating lymphocytes from TCGA, ANK2mutation was significantly associated with higher CD8+ T cells, higher M1 macrophage, and lower M2 macrophage. Moreover, ANK2 mutation was associated with increased TMB (P < 0.001) and neoantigen load (P < 0.001) in TCGA. In addition, GSEA analysis revealed that ANK2 mutation was correlated with upregulated DNA damage repair (DDR) signaling pathway in LUAD. Conclusions: Our results demonstrated that ANK2 mutation is an independent classifier that could stratify patients with NSCLC for ICIs. The role of ANK2 in immunotherapy is needed to be further studied.
Safety monitoring practice during the initiation of tyrosine kinase inhibitors (TKIs) for NSCLC treatment.
Authors: Singh Avani , Rubiera Pepe Rafael , Shafique Michael Rahman , Hicks James Kevin , Tanvetyanon Tawee 
Published: June 2022

e21090 Background: TKIs are standard treatment for non-small cell lung cancer (NSCLC) which harbors an actionable mutation. TKIs have a unique toxicity profile, distinct from conventional chemotherapy. Although the manufacturer of each TKI often issues a specific safety precaution on its label, no set schedule has been widely adopted. We surveyed the safety monitoring practice at a large academic institution. Methods: Electronic medical records of patients with ROS1, ALK or EGFR-mutated NSCLC who began a TKI during 2017-2021 were retrospectively reviewed. For each patient, the observation period started from the date of TKI prescription and lasted through day 60. Safety metrics were formulated based on drug label recommendations of each TKI. For each treatment course, the occurrence of 2 index safety monitoring activities (Table) were recorded. Results: Analysis included 130 treatment courses: 82 osimertinib, 20 alectinib, 15 crizotinib and 13 lorlatinib. Median age was 64.3 years, with 66% female, 81% white, 91% ECOG 0/1, 28% zero comorbidity, and 99% non-smoker. For osimertinib, EKG was obtained at baseline (within 30 days of treatment initiation) in 69.5% of observations, and LVEF, in 26.8%. By 60 days, these numbers barely increased (Table). Overall, absence of any index safety monitoring activity occurred in 41 of 130 (32%) treatment courses. Multivariable logistic regression analysis found a trend toward less monitoring among non-white patients: Odds ratio 0.35 (95% CI 0.11-1.09, p = 0.07). No association was found between the number of cardiac risk factors and LVEF monitoring or the use of QT prolonging medication and QTc monitoring. Conclusions: We observed a wide variation in the safety monitoring practice during TKI initiation. Deviation from the manufacturer recommendation was most pronounced for CPK monitoring in alectinib. Future study is needed to define the clinical significance of deviation and to identify barriers to safety monitoring.[Table: see text]
Prognostic significance of pleural effusion exhausted CD8+ T cell subsets in non-small cell lung cancer and mesothelioma.
Authors: Ye Linda , Dick Ian , Chiang Peter , Firth Tina , Creaney Jenette , Robinson Bruce WS , Redwood Alec 
Published: June 2022

e21111 Background: Following repeated tumor antigen stimulation, T cells lose functional capacity and become exhausted. T cell exhaustion is a progressive change in phenotype. Early in the pathway, stem-like exhausted T cells (Texstem) retain proliferative and cytotoxic potential. However, they differentiate into terminally exhausted T cells (Texterm) that become epigenetically fixed in a suppressed state and lose much of their effector function. Malignant pleural effusion is a peri-tumoral microenvironment that could offer insight into anti-tumor immune responses. In this study we characterized exhausted CD8+ T cells, examined the prognostic significance of Texstem and Texterm levels in the pleural effusions of patients with non-small cell lung cancer (NSCLC) and validated our findings in a mesothelioma cohort. Methods: Pre-treatment malignant pleural effusions from 43 NSCLC (41 non-squamous and 2 squamous) and 50 mesothelioma patients were analyzed by flow cytometry. The percentages of Texstem (PD1midCD39- or PD1midCD39-CD28+) and Texterm (PD1hi CD39+) CD8+ T cells were correlated with overall survival (OS). Survival analysis was performed using Kaplan-Meier and multivariate Cox regression analysis adjusting for age, sex, histological and molecular subtypes, performance status, smoking history, comorbidities and the number of lines of systemic therapy. Results: The relative percentages of exhausted T cells within the CD8+ T cell compartment of pleural effusions from NSCLC and mesothelioma were similar (Table). In NSCLC patients, multivariate analysis demonstrated that the percentage of Texstem was an independent predictor of OS. The median OS for patients with high (above median) Texstem was significantly longer than those with low Texstem (9.9 vs 3.4 months, HR 0.398, p = 0.020). In addition, the ratio of Texstem to Texterm also showed a positive association with OS. Similarly, in mesothelioma patients, a greater percentage of Texstem was associated with longer OS in multivariate analysis (p = 0.049). The median OS for patients with high vs low Texstem was 33.5 vs 11.1 months (HR 0.302, 95% CI 0.129 – 0.705, p = 0.006). In addition, there was also a positive association between Texstem to Texterm ratio and OS. Conversely, Texterm CD8+ T cells did not impact OS in either cancer type. Conclusions: NSCLC and mesothelioma patients with greater abundance of pleural effusion stem-like exhausted CD8+ T cells exhibit better survival outcomes irrespective of patient and disease characteristics, supporting its role as a prognostic biomarker.[Table: see text]
Development and validation of longitudinal c-reactive protein as dynamic response predictor for PD-L1 blockade in advanced NSCLC: Findings from four atezolizumab clinical trials.
Authors: Zhou Jian-Guo , Chen Xiaofei , Wong Ada Hang-Heng , Wang Haitao , Tan Fangya , He Si-Si , Shen Gang , Wang YunJia , Wang Ruihong , Carr Shamus R. , Frey Benjamin , Fietkau Rainer , Hecht Markus , Ma Hu , Schrump David S. , Gaipl Udo S 
Published: June 2022

e21113 Background: Numerous studies suggested that pre-treatment C-reactive protein (CRP) is a survival predictive biomarker for cancer patients treated with anti-PD-(L)1 blockade. However, the application of longitudinal CRP levels as dynamic biomarker for advanced non-small cell lung cancer (NSCLC) patients treated with anti-PD-(L)1 remains unexplored. Methods: This study analyzed four international, multi-center clinical trials (OAK, BIRCH, POPLAR and FIR trials) to conduct post-hoc analyses of NSCLC patients undergoing atezolizumab (anti-PD-L1) single-agent treatment. CRP test was performed ≤ 96 hours before Day 1 of each cycle. 1438 patients with more than 2 times CRP results (a total of 11,253 records) in all 3 collection timepoints. The primary endpoint was overall survival (OS). First, multivariate survival analysis was conducted to include clinical factors such as gender, ECOG-PS, race and metastases as contributing risk factors. Then, multivariate joint modelling of longitudinal and time-to-event data was used to establish the relationship between longitudinal CRP and OS in the OAK study, whereas external validation was performed by time-dependent AUC analysis on the BIRCH, POPLAR and FIR studies. Results: Log-transformed longitudinal CRP levels (log(CRP)) in combination with clinical factors in absence of PD-L1 expression emerged as independent predictors of worse OS in the OAK study (HR of jointed model = 2.08, 95% CI: 1.84-2.35, p < 0.001) with a high accuracy (AUC = 0.74) for predicting OS. The predictive value of longitudinal CRP was validated in the external validation cohorts with good performance in OS (BIRCH: HR = 2.77 (95% CI: 2.31-3.44), AUC = 0.76; POPLAR: HR = 1.95 (95% CI: 1.50-2.64), AUC = 0.76; and FIR: HR = 1.83 (95% CI: 1.46 -2.39), AUC = 0.72). Conclusions: The Bayesian multivariate joint model demonstrated that longitudinal CRP is a strong survival dynamic predictor for atezolizumab-treated NSCLC patients.
Inflammatory signals hidden in the CBC are detectable prior to durvalumab-induced pneumonitis.
Authors: DeCarli Kathryn , Masel Rebecca , Olszewski Adam J , Belani Neel , Koffer Paul , Azzoli Christopher G. 
Published: June 2022

e21116 Background: For patients with unresectable stage III non-small cell lung cancer (NSCLC), chemoradiation followed by 1 year of durvalumab is standard of care. Treatment-induced pneumonitis can be life-threatening. Neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and systemic immune inflammation index (SII, defined as platelet x neutrophil / lymphocyte counts) are calculated from the CBC and have been studied as inflammatory biomarkers in a variety of settings. This study assessed trends in these indices among patients treated for stage III NSCLC. Methods: We reviewed medical records of adults with stage III NSCLC who completed chemoradiation and durvalumab from 1/2017 to 9/2021 as part of routine care. Patients who developed non-pneumonitis immune toxicity were excluded. NLR, PLR and SII were calculated at dates of first and last radiation dose and first durvalumab dose. For patients who developed pneumonitis, indices were also calculated at each of 8 weeks leading up to pneumonitis onset, defined as the first diagnostic CT scan and graded as 1-5 based on CTCAE criteria. Indices were compared between the pneumonitis and no pneumonitis group using rank-sum test. P values < 0.05 were considered statistically significant without adjustment for multiple testing. The slope of linear trend for each index was examined via log-gamma generalized linear regression model using a random intercept for each patient and robust standard error. Results: Of 65 patients who received chemoradiation followed by durvalumab, 2 were excluded because they were on clinical trial and 28 were excluded for non-pneumonitis immune toxicity. Among the 35 patients eligible for analysis, median age was 67 years; 20 (57%) were female; 6 (17%) were current smokers; 15 (43%) had COPD; and 17 (49%) developed pneumonitis (2 G1; 11 G2; 3 G3; 0 G4; 1 G5). In the pneumonitis group, NLR (p = 0.022), PLR (p = 0.007) and SII (p = 0.001) showed a statistically significant linear increase in the 5 weeks preceding pneumonitis onset. There were no differences in clinical characteristics, SII, NLR or PLR between the pneumonitis and no pneumonitis groups at the 3 time points examined. Conclusions: In this exploratory analysis, patients who developed pneumonitis showed a linear increase in inflammatory indices for 5 weeks before pneumonitis onset, suggesting information hidden in routine blood tests can anticipate development of a life-threatening complication. Our hypothesis-generating study will need validation in a larger prospective analysis with a control group. Future directions may also include examination of selected acute phase reactants or cytokines.
Therapeutic effects and clinical outcomes of immune checkpoint inhibitors on bone metastases in lung cancer.
Authors: Asano Yohei , Yamamoto Norio , Hayashi Katsuhiro , Takeuchi Akihiko , Miwa Shinji , Igarashi Kentaro , Yonezawa Hirotaka , Morinaga Sei , Saito Shiro , Tsuchiya Hiroyuki 
Published: June 2022

e21118 Background: In recent years, advanced lung cancer patients who received immune checkpoint inhibitors (ICIs) reportedly had a more prolonged overall survival (OS) than those treated with conventional anticancer drugs. However, the therapeutic effect of ICIs on bone metastases remains unclear. The purpose of this study was to investigate the therapeutic effects of ICIs on advanced lung cancer with bone metastasis. Methods: This retrospective study included 58 lung cancer patients (42 men and 16 women; mean age, 66.2±7.8 years) who had been diagnosed with bone metastasis before the initiation of ICI treatment between 2016 and 2019, and the mean follow-up period was 23.2 months. The clinical data such as content of chemotherapy including the bone-modifying agent (BMA), skeletal-related events (SREs), and immune-related adverse events (irAEs) were investigated. The therapeutic effects of ICIs on the primary lung lesions and bone metastases were evaluated by the response evaluation criteria in solid tumors 1.1 (RECIST 1.1) and MD Anderson criteria, respectively. To assess the influence of ICI treatment on prognosis, OS from the diagnosis of bone metastases was compared to the prognostic prediction of Katagiri's score. Results: The most used ICI was pembrolizumab in 27 cases (46.6%). BMA was used in 38 cases (65.6%), and denosumab was used in 31 cases (81.6%). SREs and irAEs were observed in three cases (5.2%) and 13 cases (22.4%), respectively. In the primary lung lesions, the response rate (RR) and disease control rate (DCR) of ICIs were 14.3% and 38.1%, respectively, including one case in CR and 5 cases in PR. In the bone metastatic lesions, the RR and DCR were 38.6% and 75.0%, respectively, including 3 cases in CR and 14 cases in PR. In 17 cases that ICIs responded to bone metastases, nine cases were treated with pembrolizumab (52.9%), and all cases whose evaluations were CR had been treated with concomitant therapy of pembrolizumab and denosumab. The median survival time was 28.1 months and the 2-year OS rate was 51.7%. The 6-, 12-, and 24-month OS rates in this study were more favorable than the prognostic prediction of the Katagiri's score. Conclusions: ICI treatment showed favorable responses to bone metastases in NSCLC and better prognoses than conventional predictive prognosis. Particularly, pembrolizumab may be the most effective, and the therapeutic effect was enhanced by the concomitant use of denosumab.[Table: see text]
Medication use among lung cancer patients before and after initiating immune checkpoint inhibitors: A population study.
Authors: Mei Chuchu , Yang Amy , Shaver Amy L , Nikita Nikita , Banks Joshua , Keith Scott W. , Lu-Yao Grace L. 
Published: June 2022

e21119 Background: Polypharmacy is an independent prognostic factor in older patients with lung cancer treated with immune checkpoint inhibitors (ICIs). Previous studies have shown that steroids, opioids, proton pump inhibitors, fluoroquinolone are associated with worsening overall survivals for lung cancer patients. The prevalence of drug use among lung cancer patients using ICIs is understudied. Methods: The study population consisted of older adults (aged 65 years or older) diagnosed with lung cancer from January 1, 2011, to December 31, 2016, in the Surveillance, Epidemiology, and End Results–Medicare linked database. Patients with a diagnosis of lung cancer and a claims record showing nivolumab plus ipilimumab combination therapy or anti–PD-1 therapy (ie, pembrolizumab or nivolumab) as their ICI prescribed were included in the analyses. Index date was defined as the date of first dose of ICIs. We examined medication usage within 90 days prior and after index date. Drug categories were classified, by mechanism of action from Lexicomp®, using Medicare Part D Drug event generic name. Descriptive analysis was used to show the percentage of concurrent drug usage for each drug category. McNemar test was used to compare the drug use prevalence before and after index day. Results: There are 669 patients in the study (male [48.56%], 65–74-year-old [67.10%]). Usage of steroids (89.09%), opioids (87.89%) was high before ICIs. Significant decreases were observed between before and after the index day for most prescribed drug categories, including anti-psychotics (-62.94%, p < .0001). But the use of thyroid products (35.83%, p < .0001) increased in usage after starting ICIs. Conclusions: To our knowledge, this is the first population-based study to quantify concurrent medication use amongst lung cancer patients undergoing immunotherapy. This study suggests the polypharmacy decreased significantly after initiation of ICIs. Future studies are required to investigate the reasons for the changes in medication use and increased utilization of thyroid products.[Table: see text]