bluuebunny/crossref_metadata_2025_split huggingface dataset:
Driver mutations and air pollution in advanced non-small cell lung cancer (NSCLC) at two reference hospitals in Mexico City.
Authors: Sanchez Eduardo , Trejo Rosales Raul Rogelio , Remolina Bonilla Yuly Andrea , Sánchez Hernández Juan José , Vélez Martínez Amairany Guadalupe , De Jesus Hernandez Dulce Angelica , Najar Miriam , Lizcano Aguilar Nestor Javier , Hernandez Castillo Marco Antonio , Cruz Andrea , Zarroca Palacio Santiago 
Published: June 2022

e20545 Background: Currently, precision medicine has allowed the classification of NSCLC according to the profile of driver mutations and the development of highly effective treatments. There is evidence to support the relationship between outdoor air pollution, particularly particulate matter (PM) in outdoor air, with lung cancer incidence and mortality. Smoking is a negative predictor of EGFR mutation, but the effect of air pollution has not been stablished. Methods: We perform a retrospective study in two referral hospitals in Mexico City between 2015 to 2020 to determinate the frequency of key driver mutations in patients with advanced NSCLC and the relation with smoking habit, wood smoke exposure and pollution indexes (PM2.5, PM10, SO2, O3, NO2) according to their place of residence. We used WHO air quality thresholds for air pollutants to classify cases with high or low exposure. Results: A total of 1277 cases were analyzed. The median age at diagnosis was 66 years (range 18-97 years), 53% were females and 49.6% had history of smoking habit. According to histology, 61.6% of cases corresponded to adenocarcinoma, 11.7% were squamous, 1.3% large cell, and 25.4% indeterminate. Wood smoke was assessed in 83.1% of cases and 28.5% had exposure history. Air pollutants were measured in half of cases, high level of exposure for PM2.5, PM10, NO2 and SO2 occurred in 63.2%, 30.8%, 15.6%, 53.4%, respectively. EGFR, ALK and KRAS mutations were evaluated in 85%, 16.7% and 8.6% of patients, respectively. The presence of these mutations was: EGFR 17.1%, ALK 11.1%, and KRAS 16.5%. Patients with EGFR-positive NSCLC were more frequently female (65.1% vs 34.9%, OR 1.8 95%CI 1.4-2.5, p < 0.001) and had no history of tobacco use (35% vs 65%, OR 0.49 95%CI 0.36-0.67, p < 0.001). Wood smoke was not statistically significant. High exposure to PM2.5 was most common in patients with non-mutated EGFR NSCLC (65.3% vs 34.7%, OR 1.7 95%CI 1.2-2.5, p = 0.006). Relationship with other air pollutants were not statistically significant. ALK-positive NSCLC patients tend to be females (68% vs 32%, p = 0.07) and had no history of smoking habit (20.8% vs 79.2% OR 0.28 95%CI 0.1-0.78, p = 0.01). High exposure to SO2 was common (78.6% vs 21.4% p = 0.05). Association in KRAS-positive NSCLS patients were not found. Conclusions: A low rate of key driver mutations assessment was found in this Mexican cohort. Clinical profile of NSCLC EGFR positive is according with previous reports in the literature. Exposure to PM2.5 and SO2 were found associated with EGFR and ALK status in this retrospective study and are hypothesis generating information.
Circulating nucleosomes to identify non-smoker subjects at risk of lung cancer and triage them for low-dose CT scan.
Authors: Tsai Tung-Ming , Hardat Nathalie , Pamart Dorian , Herzog Marielle , Chen Jin-Shing 
Published: June 2022

e20558 Background: Lung cancer (LC) is the leading cause of cancer death worldwide and the most frequently occurring in men and the second most diagnosed cancer in woman after breast cancer. The primary risk factor leading to LC is tobacco smoke. Nevertheless, several studies in the US, UK and Asia reported an increasing rate of LC in non-smokers. 15-20% of LC patients worldwide are non-smokers with this percentage rising to 60% in non-smoking women in Asia. Current LC screening guidelines recommend a CT scan only for high-risk smokers. Despite there being no guidelines to recommend LC screening in non-smokers those with increased risk factors could be monitored. Therefore, a blood-test could offer a simple way to identify non-smokers at high-risk of LC and triage them to go for low-dose CT scan. Methods: We measured circulating levels of nucleosomes and CEA in 722 non-smoker subjects referred for CT scan at National Taiwan University Hospital. The patients were later confirmed to have either a LC (n = 509, including 401 patients at stage 0-1), non-malignant nodules (n = 142), or no-nodules (n = 71). Whole blood was collected in EDTA plasma tubes for analysis by six different Nu.Q chemiluminescent magnetic microparticle immunoassays (Belgian Volition SRL, Belgium) targeting H3.1-nucleosomes or different histone modifications (H3K9Me3-, H3K27Me3-, H3K36Me3-, H3K9Ac-, H3K14Ac-nucleosomes). CEA was analyzed on the Abbott ARCHITECT analyzer. We defined by logistic regression the best combination of biomarkers to identify LC cases in this non-smoking population in a rule-in approach. Results: At 95% specificity, none of the individual biomarkers exceed 24.8% of sensitivity for LC vs non-malignant nodules and no nodules. A combination of 2 nucleosome biomarkers: H3K9Me3- and H3K9Ac-nucleosomes with CEA in a logistic regression model showed improved sensitivity detecting 32.4% of LC in the non-smoker subjects at 95% specificity for LC vs non-malignant nodules and no nodules (area under the curve (AUC): 0.76, R2: 19.1%). In a non-smoking women sub-group by adding a third nucleosome biomarker: H3K36Me3-nucleosomes to the model we could detect 34.3% of the women who have lung cancer at 95% specificity (AUC: 0.75; R2: 20.2%). Conclusions: Our results indicate that a blood test combining circulating nucleosomes targeting different epigenetic modifications with CEA allow the detection of LC cases in a non-smokers population. This blood test could be part of the screening criteria for the non-smoking population at risk to develop LC and could help to triage them for low-dose CT scan.
Association of TP53 polymorphisms with the acquisition of EGFR T790M mutations in patients with first- or second-generation EGFR-TIK progression.
Authors: Dong Huajie , Zhou Tong , Li Peng , Wu Changling , Lu Hongjun , Zhao Lele , Yang Xueyu , Deng Wanglong , Qi Chuang 
Published: June 2022

e20560 Background: Lung cancer is the leading cause of cancer death worldwide. EGFR tyrosine kinase inhibitors (TKIs) has transformed management in those patients. However, the majority of patients will become resistant to EGFR-TKIs after a period of time. The T790M acquired mutation in exon 20 of the EGFR is the predominant molecular mechanism of acquired resistance. In first-line treatment of global patients with NSCLC, osimertinib had better efficacy compared to first-generation TKIs. In the FLAURA study, the median PFS with first-line osimertinib in Asians was only 16.5 months, compared to 18.6 months in the global population. Moreover, the OS benefit in the Asian population was relatively small. At the same time, the mechanism of resistance to osimertinib is very complex and patients have limited treatment options after first-line osimertinib resistance. A variety of factors can influence the decision for first-line treatment in EGFR mutation-positive patients, including follow-up regimens, the presence of brain metastases, and tolerability, all of which should be considered in the long-term treatment plan. Knowing in advance whether patients are likely to acquire EGFR T790M mutations will help in making treatment decisions. Previous studies have shown that TP53 Arg72Pro polymorphism (rs1042522) is associated with the risk and prognosis of lung cancer. Currently, the association between EGFR mutations and TP53 polymorphisms is unclear, but previous reports have suggested that patients with EGFRmutation demonstrated a higher rate of TP53 mutation than EGFR wild type patients. Therefore, this study aim to explore the association of TP53 polymorphisms (rs1042522) with EGFR T790M acquired mutations, considering the value of T790M in lung cancer treatment. Methods: We analyzed two independent cohorts of patients with EGFR-mutant NSCLC who progressed after first-line EGFR-TKIs treatment from 2013 to 2021 (cohort 1: n=108; cohort 2: n=148). All patients were tested with plasma next-generation sequencing (NGS). Results: The acquired T790M mutation rate was 36%, 30% and 43% in all patients (n = 256), cohort 1 and cohort 2, respectively. Logistic regression analysis showed that TP53 rs1042522 polymorphism was significantly associated with an increased risk of T790M acquired mutation in cohort 1 (GG versus CC: OR (95% CI) = 3.57 (1.15-12.2), P = 0.033) and cohort 2 (GG versus CC: univariable OR (95% CI) = 3.53 (1.30-10.3), P = 0.016; multivariable OR (95% CI) = 2.94 (1.04-8.87), P= 0.047). Conclusions: We found that the TP53 rs1042522 polymorphism GG was associated with EGFR T790M acquired mutations. Knowing in advance whether patients are likely to acquire EGFR T790M mutations will help in making treatment decisions.
Dysregulated Th1 cells in lung squamous cell carcinoma.
Authors: Wang Jiahui , Zhou Qiuru , Yan Cihui , Hui Zhenzhen , Wang Tao , Zheng Liuqing , Xiao Shanshan , Zhou Jian , Zhao Yu , Wang Zhe , Ren Yulin , Wang Hao , Ren Xiubao 
Published: June 2022

e20566 Background: Lung squamous cell carcinoma (LUSC) is one of the most common subtypes of lung cancer which lacks of effective treatments compared to lung adenocarcinoma. The Th1 subset in CD4+ T cells plays an indispensable role in antitumor immune responses. However, there are few studies on Th1 cells in LUSC. Methods: Firstly, we used single-cell RNA-seq to analyze the gene expression in 8 LUSC patients’ tissues, including tumor tissues, paracancerous tissues, normal tissues, lymphoid tissues, pre-treatment blood samples and pre-operative blood samples. A total of qualified 44969 CD4+ T cells and 22971 Th1 candidate cells (Because STAT1, STAT4 and T-bet can promote IFN-γ expression. We define CD4+ T cells with one or more of above four indicators as Th1 candidate cells (Th1 CDD cells)) were identified. Then, we validated Th1 CDD cells and CD8+ T cells of tumor sites in 32 patients with LUSC by using multiplex immunofluorescence staining and immunohistochemistry. Finally, we used flow cytometry to detect the IFN-γ of CD4+ T cells in human PBMCs which were co-incubated with the supernatant derived from LUSC cell lines to simulate the tumor inhibitory microenvironment. Results: Single cell RNA-seq results showed IFN-γ+ Th1 CDD cells only account for about 25.28% of the total Th1 CDD cells. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of the differentially expressed genes (DEGs) between IFN-γ+ Th1 CDD cells and IFN-γ- Th1 CDD cells demonstrated that the decreased level of IFN-γ expression was associated with ribosomes, antigen presentation, cell-to-cell interactions, apoptosis, endoplasmic reticulum stress (ER stress) and so on. According to multiplex immunofluorescence staining and immunohistochemistry, there was a positive correlation between the IFN-γ+ STAT1+ T-bet+ Th1 CDD cells and CD8+ T cells in tumor stromal compartment. Flow cytometry showed decreased level of IFN-γ in Th1 cells co-incubated with LUSC-derived supernatant. Conclusions: The function of Th1 CDD cells is suppressed in LUSC. In our study, we found that the decreased function of Th1 CDD cells is associated with ER stress by single cell RNA-seq, which requires further research. Overall, this may highlight a new target for the treatment of LUSC.
Impact of pretreatment clinical factors and DVH parameters on radiation pneumonitis and survival after intensity-modulated radiotherapy for lung cancer.
Authors: Liang ZiBin , Xu Xiaolu , Guo Shuanshuan , Niu Xiaoli , Yan Lubin , Zou Yanfei , Lin Zhong , Peng Peijian , Wang Zhihui , Hu Liyang 
Published: June 2022

e20571 Background: The aim of this study was to investigate the relationship between clinical factors and dose-volume histogram parameters regarding Overall Survival (OS) and Radiation-Pneumonitis-Free Survival (RPFS) in lung cancer patients. Methods: We retrospectively reviewed clinical data of lung cancer patients from 2018 to 2020. Demographic, clinical, and treatment-related data were collected for all patients. OS was defined as the duration from pathological diagnosis to death or last follow-up. RPFS was defined as the duration from the start of radiation therapy to occurrence of grade≥3 Radiation-Pneumonitis, or final follow-up. RPFS and OS rates were estimated with the Kaplan-Meier method and compared using the log-rank test. The Cox regression model was used to estimate the hazard ratio (HR) and the corresponding 95% confidence interval (CI) for univariate and multivariate analysis. Results: A-hundred patients were included in this study. The median follow-up period after completion of radiotherapy was 42.9months (range: 2.0–152.1). In multivariate study, low serum sodium after RT, V5ipsi≥51%, V20ipsi≥28%, V30ipsi≥22% and MLDipsi≥15.99 Gy were independent predictive factors for poor OS, respectively ( p ＜0.05). MLD≥10.20 Gy suggested a poorer RPFS ( p ＜0.1) in this cohort. Conclusions: The independent significant risk factors of radiation pneumonitis were V20, V5 and MLD. In addition, the V20 and V5 of the ipsilateral lung should be more strictly limited to less than 28% and 51% when determining radiotherapy especially in this era of immunotherapy. Some blood indexes of low nutritional status were very important to determine the occurrence of high-risk radiation pneumonitis.
Exploratory radiomic analysis of stage III non-small cell lung cancer CT images: Correlation with clinical-pathological characteristics.
Authors: Pasello Giulia , Ferro Alessandra , Scagliori Elena , Gennaro Gisella , Costa Matilde , Sepulcri Matteo , Schiavon Marco , Bonanno Laura , Frega Stefano , Caumo Francesca , Calabrese Fiorella , Rea Federico , Guarneri Valentina 
Published: June 2022

e20574 Background: Recent evidences have suggested potential applications of radiomics in early diagnosis, prognostic stratification and treatment outcome prediction of Non-Small Cell Lung Cancer (NSCLC) patients. The purpose of this study is to evaluate the ability of radiomic analysis to discriminate between different clinical-pathological conditions in patients with stage III NSCLC. Methods: Baseline CT studies from 59 patients with stage III NSCLC referred to our Institution from 2010 and 2020 were retrospectively reviewed, and the segmentation of the main lung lesion and the extraction of 517 radiomic features performed using a commercial software. The number of features was reduced to 46 by means of principal component analysis applied using the R package “RadAR” (Radiomics Analysis with R). The Kruskal-Wallis test was applied to all the radiomic features in order to evaluate which of them can discriminate between 7 clinical dichotomous characteristics: tumor stage, type, presence of mutation, treatment response, relapse free survival (RFS), smoking habit, patient outcome. P < 0.05 means that there is a statistically significant difference between the two subgroups. Results: The median age at diagnosis was 69 years (range 43-83). Most patients were males (40/59 = 67.8%) and heavy smokers (36/59 = 61.0%). Adenocarcinoma was the most common histology (41/59 = 70.7%), while cases were almost equally splitted between stage IIIA (45.8%) and stage IIIB or IIIC (54.2%). Most selected radiomic features (29/46 = 63.0%) showed a statistically significant difference between patients with and without mutations. Ten (10/46 = 21.7%) radiomic features were associated with patient sex. Seven features (7/45 = 15.2%) were “sensitive” to the tumor clinical stage (stage IIIA vs. stage IIIB+IIIC), 4 (4/46 = 8.7%) to the histological type, and 2 (2/46 = 4.3%) to the patient outcome. None of the selected radiomic features was able to discriminate between responder and non-responder patients, current/previous smokers and never smokers, and patients with RFS lower than 12 months versus RFS equal or higher than 12 months. Conclusions: This preliminary analysis showed that radiomics has the potential of identifying mathematical features associated with clinical and histopathological characteristics in stage III NSCLC patients, which might feed multiparametric predictive models. Larger datasets and further analysis are necessary in order to confirm initial results.
Characterizing node-negative non-small cell lung cancer patients with similarity networks: A CancerLinQ Discovery analysis.
Authors: Moen Erika L , Chen Zoe , Schaefer Andrew , Bhimani Alisha , O'Malley James , Dragnev Konstantin H. 
Published: June 2022

e20585 Background: Patients with node-negative non-small cell lung cancer (NSCLC) whose tumors are completely resected account for approximately 17% of all patients with lung cancer, and disease recurrence occurs in approximately 1 in 5 of these patients. The lack of consensus on factors associated with risk of disease recurrence among node-negative NSCLC patients is a significant barrier to applying precision medicine strategies in this patient population. Clustering similar patients based on distances between various features of data is an emerging topic in precision medicine. Patient similarity networks represent a new model for clustering patients based on heterogeneous data, whereby any data type is converted into a similarity network by defining a similarity measure. The objective of this study was to examine the utility of patient similarity networks to identify NSCLC patients at higher risk of adverse outcomes. Methods: We conducted a retrospective, observational study of 6,020 node-negative NSCLC patients with an initial diagnosis in 2011-2014 in the CancerLinQ Discovery database. A patient similarity network was assembled based on comorbidities and network communities of patients with similar comorbidities at diagnosis were identified. Using Cox proportional-hazards modeling, we examined the extent to which patient age, sex, race, ethnicity, and network community predicted 2-year disease recurrence and 2-year mortality. Results: In the adjusted analyses, patients in the network community enriched for renal disease and congestive heart failure had an 83% increased risk of mortality (95% CI = 1.39-2.41). Patients in the network community enriched for pulmonary disease had a 37% increased risk of mortality (95% CI = 1.06-1.74) yet a lower risk of recurrence (HR = 0.5, 95% CI = 0.34-0.75). After adjusting for comorbidity network community, male patients had a 14% increased risk of mortality (95%CI = 1.02-1.28) and a 21% increased risk of recurrence (95% CI = 1.05-1.40) and black patients had a lower mortality risk (HR = 0.71, 95% CI = 0.58-0.86). Conclusions: Future studies applying patient similar networks to integrate additional diverse and high dimensional data types may afford more clarity in assigning risk of adverse outcomes.
Phase 1 first-in-human trial of MTB-9655, the first oral inhibitor of ACSS2, in patients with advanced solid tumors.
Authors: Perets Ruth , Geva Ravit , McKean Meredith , Goutopoulos Andreas , Erez Omri , Phadnis Monica , Youssoufian Hagop , Schwartz Brian E. , Kansra Vikram , Fattaey Ali 
Published: June 2022

e20609 Background: ACSS2 catalyzes the ligation of acetate with Co-enzyme A to generate Acetyl-CoA. Selection to an acetate dependent state has been demonstrated and is associated with the induction of ACSS2 gene expression in certain human cancers. The ACSS2 gene is amplified in human breast cancers, and its expression is up-regulated in human colorectal, breast, ovarian and lung cancers. MTB-9655 is a potent (IC50 = 0.15nM in biochemical, and EC50 = 3nM in cellular assays) oral inhibitor of ACSS2 and induces anti-tumor effects in xenograft mouse models of human colorectal, breast and lung cancers that express high levels of ACSS2. Methods: Using a combined accelerated (single patient for the first two dose levels) and 3+3 dose escalation and dose expansion design, MTB-9655 was administered on a once daily (QD) schedule in 21-day cycles in a Phase 1 trial to assess safety, tolerability, PK and potential anti-tumor activity in patients with advanced solid tumors. Re-staging was performed every 2 cycles. Results: To-date, 10 subjects have received MTB-9655 at doses up to 225mg. MTB-9655 was absorbed rapidly post oral dosing with a half-life of 6-12 hours. Dose proportional exposure was observed on day 1 of the first dosing cycle, and steady-state exposure was noted between day 8 and day 1 of the second dosing cycle. Dose limiting toxicities or Grade 3 treatment-related adverse events (AEs) have not been observed up to the 225mg dose level. The most common AE was nausea (29%). Low grade increase in bilirubin levels was observed in 1 patient at 225mg dose, without changes in other liver enzyme levels. Increased bilirubin levels were readily reversed with dose interruption. As MTB-9655 is a 729nM inhibitor of the UGT1A1 enzyme, the increase in bilirubin levels is likely attributed to off-target UGT1A1 inhibitory activity. Conclusions: MTB-9655 has been well tolerated, and the safety profile was predictable based on preclinical studies in rodents and non-human primates. Dose proportional plasma drug levels were observed and predicted to have reached biologically active levels. Expected increase in bilirubin levels was observed in 1 patient, which may be used as a marker of significant drug exposure. MTD has not reached up to the 225mg dose and the dose escalation is continuing. Development of MTB-9655 is planned as a single agent, and based on animal model studies, in combination with standard of care platinum-based agents and gemcitabine. Clinical trial information: NCT04990739.
Effect of EGFR amplification on survival of patients with EGFR mutation-positive non-small cell lung cancer.
Authors: Xu Yiquan , Wang Haibo , Zheng Xinlong , Lin Gen 
Published: June 2022

e21000 Background: Epidermal growth factor receptor (EGFR) mutation is a common mutation in non-small cell lung cancer (NSCLC). Patients with EGFR mutation generally respond well to EGFR-tyrosine kinase inhibitors (EGFR-TKIs). EGFR mutation are often co-occurring with EGFR amplification. However, the effect of EGFR amplification on the survival of patients with EGFR mutations remained unclear. Methods: Treatment-naïve adult patients with advanced NSCLC and EGFR mutation confirmed by next generation sequencing (NGS) at Fujian Provincial Hospital between April 2017 and October 2021 were enrolled in this retrospective clinical study. The patients’ clinical characteristics, gene mutations, treatment and clinical outcomes were extracted. progression-free survival (PFS) and overall response rate (ORR) were compared between EGFR amplification and non-EGFR amplification groups using the Kaplan-Meier method and log-rank test. Results: EGFR amplification and non-EGFR amplification were identified in 55 patients (36.67%) and 95 patients (63.33%), and there were no significant differences in clinical characteristics. No significant differences between the EGFR amplification and non-EGFR amplification groups in median PFS (247 vs. 214 days, P = 0.605). The ORR in EGFR amplification group is higher than non-EGFR amplification group (60.87% vs 32.69%). Conclusions: There is a tendency that EGFR amplification might not be a well predictor in EGFR mutation positive NSCLC patients treated with EGFR-TKIs.